JP2012510441A - Arylcyclohexyl ethers of dihydrotetraazabenzoazulenes for use as vasopressin-mediated receptor antagonists - Google Patents

Abstract

The present invention provides an aryl cyclohexyl ether of a dihydrotetraazabenzoazulene derivative of formula (I) wherein R ¹ , R ² and R ³ are as described herein, ie The present invention relates to arylcyclohexyl ethers of 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene derivatives. The compounds of the invention relate to their manufacture, pharmaceutical compositions containing them and their use as medicaments, which act as V1a receptor modulators and in particular as V1a receptor antagonists. Active compounds of the present invention include dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormality, cirrhosis, nephrotic syndrome, anxiety, depression disorder, obsessive compulsive disorder, autism spectrum disorder It is useful as a treatment that acts peripherally and centrally on schizophrenia and aggressive behavioral pathologies.

Description

  The present invention relates to aryl cyclohexyl ethers of dihydrotetraazabenzoazulene derivatives, ie 5,6-dihydro-4H-2,3,5,10b-tetraaza, which act as V1a receptor modulators and in particular as V1a receptor antagonists. -Aryl cyclohexyl ethers of benzo [e] azulene derivatives, their preparation, pharmaceutical compositions containing them and their use as medicaments.

TECHNICAL FIELD The active compounds of the present invention include dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormality, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism It is useful as a treatment that acts peripherally and centrally on spectrum disorders, schizophrenia and aggressive behavioral pathologies.

  In particular, the present invention provides compounds of formula (I):

［式中、Ｒ^１、Ｒ^２及びＲ^３は、本明細書中に記載されているとおりである］で示されるジヒドロテトラアザベンゾアズレン誘導体のアリールシクロヘキシルエーテルに関する。

[Wherein R ¹ , R ² and R ³ are as described herein] relates to an arylcyclohexyl ether of a dihydrotetraazabenzoazulene derivative represented by:

Background Art Vasopressin is a 9 amino acid peptide produced mainly by the paraventricular nucleus of the hypothalamus. In the periphery, vasopressin acts as a neurohormone to stimulate vasoconstriction, glycogenolysis and antidiuretic effects.

  Three vasopressin receptors are known, all of which belong to class I G-protein coupled receptors. V1a receptor is expressed in brain, liver, vascular smooth muscle, lung, uterus and testis, V1b or V3 receptor is expressed in brain and pituitary, V2 receptor regulates water reabsorption and It is expressed in the kidney that mediates the diuretic effect of vasopressin (Robben, et al. (2006). Am J Physiol Renal Physiol. 291, F257-70, "Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus "). Therefore, compounds having activity at the V2 receptor can cause side effects on blood homeostasis.

  Oxytocin receptors are involved in the vasopressin receptor family and mediate the action of the neurohormone, oxytocin, in the brain and periphery. Oxytocin is thought to have a central anxiolytic effect (Neumann (2008). J Neuroendocrinol. 20, 858-65, “Brain oxytocin: a key regulator of emotional and social behaviors in both females and males”). Thus, central oxytocin receptor antagonism can lead to anxiety-inducing effects that are considered undesirable side effects.

  In the brain, vasopressin acts as a neuromodulator and rises in the amygdala during stress (Ebner, et al. (2002). Eur J Neurosci. 15, 384-8., “Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats "). Stressful life events can cause major depression and anxiety (Kendler, et al. (2003). Arch Gen Psychiatry. 60, 789-96, "Life Event Dimensions of Loss, Humiliation, Entrapment, and Danger in the Prediction of Onsets of Major Depression and Generalized Anxiety ") and anxiety often precedes major depression, and both are known to have high addiction (Regier, et al. (1998). Br J Psychiatry Suppl. 24-8, "Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders"). V1a receptors are widely expressed in the brain and in marginal regions such as the amygdala, lateral septum and hippocampus, which play an important role in the regulation of anxiety in particular. Indeed, V1a knockout mice show reduced anxiety behavior in the cross-maze, open field and light-dark box (Bielsky, et al. (2004). Neuropsychopharmacology. 29, 483-93, “Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice "). Down-regulation of the V1a receptor using antisense oligonucleotide injection into the septum also causes a reduction in anxiety behavior (Landgraf, et al. (1995). Regul Pept. 59, 229-39., "V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats "). Vasopressin or V1a receptors are also implicated in other neuropsychological disorders: Recent genetic studies have linked the sequence polymorphism of the human V1a receptor promoter to autism spectrum disorders (Yirmiya, et al. (2006). 11, 488-94, "Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills"), intranasal administration of vasopressin to human men (Thompson, et al. (2004). Psychoneuroendocrinology. 29, 35-48, "The effects of vasopressin on human facial responses related to social communication") and vasopressin levels are schizophrenia (Raskind, et al. (1987). Biol Psychiatry. 22, 453-62, "Antipsychotic drugs and plasma vasopressin in normals and acute schizophrenic patients") and obsessive compulsive disorder (Altemus, et al. (1992). Arch Gen Psychiatry. 49, 9-20, "Abnormalitie s in the regulation of vasopressin and corticotropin releasing factor secretion in obsessive-compulsive disorder ”).

  V1a receptors also mediate the cardiovascular effects of vasopressin in the brain by centrally regulating blood pressure and heart rate in the solitary nucleus (Michelini and Morris (1999). Ann NY Acad Sci 897, 198-211, "Endogenous vasopressin modulates the cardiovascular responses to exercise"). In the periphery, V1a receptor induces vascular smooth muscle contraction and chronic inhibition of V1a receptor improves hemodynamic parameters in rats with myocardial infarction (Van Kerckhoven, et al. (2002). Eur J Pharmacol 449, 135-41, "Chronic vasopressin V (1A) but not V (2) receptor antagonism prevents heart failure in chronically infarcted rats"). Thus, V1a antagonists with improved permeability across the blood brain barrier are expected to be advantageous.

  Vasopressin V1a receptor antagonists have been shown in clinical studies to be effective in reducing dysmenorrhea (Brouard, et al. (2000). Bjog. 107, 614-9, "Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhoea "). V1a receptor antagonism has also been implicated in the treatment of female sexual dysfunction (Aughton, et al. (2008). Br J Pharmacol. Doi: 10.1038 / bjp.2008.253, " Pharmacological profiling of neuropeptides on rabbit vaginal wall and vaginal artery smooth muscle in vitro "). Recent studies have suggested that V1a receptor antagonists have a therapeutic role in both erectile dysfunction and premature ejaculation (Gupta, et al. (2008). Br J Pharmacol. 155, 118-26, "Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V (1A) receptor and not oxytocin receptor").

DETAILED DESCRIPTION OF THE INVENTION It is an object of the present invention to provide compounds that act as V1a receptor modulators and in particular as V1a receptor antagonists. A further object of the present invention is to provide selective inhibitors of the V1a receptor, since its selectivity is expected to reduce the likelihood of adverse off-target related side effects as described above. It is to be.

  Such V1a antagonists include dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depression disorder, obsessive compulsive disorder, autism spectrum disorder, integration It is useful as a treatment that acts peripherally and centrally in the pathology of ataxia and aggressive behavior. Preferred indications for the present invention are the treatment of anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive behavior.

  V1a activity can be detected as described in the test section.

  The following definitions of common terms used herein apply regardless of whether such terms appear alone or in combination.

As used herein, the term “alkyl”, alone or in combination with other groups, means a saturated, ie, aliphatic, hydrocarbon group containing a straight or branched carbon chain. If not otherwise specified, an “alkyl” group means a group having 1-12 carbon atoms, such as “C _1-12 -alkyl”. “C _1-4 -alkyl” refers to an alkyl group having 1 to 4 carbon atoms, and “C _1-7 -alkyl” refers to an alkyl group having 1 to 7 carbon atoms. Examples of “alkyl” are methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and the like. Preference is given to methyl and tert-butyl.

The term “alkoxy”, alone or in combination with other groups, refers to a group —O—R ′, where R ′ is alkyl as defined above. “C _1-12 -alkoxy” denotes an alkoxy group having 1 to 12 carbon atoms, “C _1-4 -alkoxy” denotes an alkoxy group having 1 to 4 carbon atoms, and “ “C _1-7 -alkoxy” means an alkoxy group having 1 to 7 carbon atoms. Examples of “alkoxy” are methoxy, ethoxy, propoxy, tert-butoxy and the like. Preferred is methoxy.

  The term “aromatic” means the presence of an electron hexat in the ring according to Hückel's rule.

  The term “aryl”, alone or in combination with other groups, means a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring. Preferred aryl is phenyl or naphthyl. Aryl can be unsubstituted or substituted as described herein.

  The term “cyano” refers to the group —CN.

  The term “hydroxy” refers to the group —OH.

  The term “halo” or “halogen” means chloro, iodo, fluoro and bromo.

The term “halo-C _1-n -alkyl” or “C _1-n -haloalkyl”, alone or in combination with other groups, has _1-n carbon atoms as defined herein. Means a C _1-n -alkyl group as defined above, wherein at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro. Examples of halo-C _1-n -alkyl include, but are not limited to, methyl, substituted with one or more Cl, F, Br or I atoms, in particular with 1, 2 or 3 fluoro or chloro. Including ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl, and those groups specifically exemplified in the examples herein below. Preferred halo-C _1-n -alkyl groups include difluoro- or trifluoro-methyl or -ethyl.

The term “hydroxy-C _1-n -alkyl” or “C _1-n -hydroxyalkyl”, alone or in combination with other groups, has 1 to n carbon atoms, as defined above for C _{1. -N} means an alkyl group, wherein at least one hydrogen atom of the alkyl group is replaced by hydroxy, ie an OH group. An example of hydroxyalkyl is hydroxyethyl.

  The terms “heteroaryl” and “5- or 6-membered heteroaryl”, alone or in combination with other groups, contain from 1 to 4 ring heteroatoms selected from N, O, or S, and the rest A monovalent 5-membered or 6-membered monocyclic aromatic ring, or a 9-membered or 10-membered bicyclic aromatic ring, wherein the ring atom is C. Preferably, the monocyclic heteroaryl has 1 or 2 heteroatoms and the bicyclic heteroaryl has 1 to 4 heteroatoms. 6-membered heteroaryl is preferred. Examples as heteroaryl moieties include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl. A heteroaryl may be unsubstituted or substituted as described herein.

  The term “heterocycloalkyl”, as defined herein, alone or in combination with other groups contains one or two heteroatoms selected from N, O or S. , Monovalent 3- to 7-membered or 4- to 7-membered saturated ring. The term “3- to 7-membered heterocycloalkyl” refers to a monovalent 3- to 7-membered ring containing 1 or 2 heteroatoms selected from N, O or S. Examples of heterocycloalkyl moieties are oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl or piperazinyl. Preferred heterocycloalkyl are oxetanyl and tetrahydrofuranyl. Heterocycloalkyl is optionally substituted as described herein.

The term “oxo” when referring to a substituent on a heterocycloalkyl means that an oxygen atom is attached to the heterocycloalkyl ring. Thus, “oxo” replaces two hydrogen atoms on a carbon atom, or such that sulfur exists in an oxidized form, ie, having one or two oxygens such as the group —SO ₂ . Oxo can be either simply bound to sulfur.

  When referring to the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, ie from the replacement of one hydrogen by a substituent to the replacement of all hydrogens. To do. Accordingly, 1, 2 or 3 substituents are preferred. Even more preferred is 1 or 2 substituents or 1 substituent.

  The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable acid addition salt” refers to hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid. And salts with inorganic and organic acids such as methanesulfonic acid, p-toluenesulfonic acid and the like. Preference is given to the hydrochloride.

  The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

  The term “pharmaceutical composition” includes products that contain a particular component in a predetermined amount or ratio, and any product that results from combining a particular component in a particular amount, either directly or indirectly. . Preferably, it comprises a product comprising one or more active ingredients and any carrier comprising inert ingredients, and directly or indirectly, from a combination, complexation or aggregation of any two or more ingredients, or Any product resulting from the dissociation of one or more components, or from the reaction or interaction of one or more components in other forms is included.

  The following table lists the abbreviations used in this specification.

  The invention also provides pharmaceutical compositions, methods of use and methods of preparing the above-described compounds.

  The compound of formula (I) may contain an asymmetric carbon atom. Accordingly, the present invention includes all stereoisomeric forms of the compounds of formula (I), including each individual stereoisomer and mixtures thereof, ie the individual optical isomers and mixtures thereof. Additional asymmetric centers can exist depending on the nature of the various substituents on the molecule. Each such asymmetric center independently yields two optical isomers, and all possible optical isomers and diastereomers in mixtures and pure or partially purified compounds are included in the present invention. Intended. The present invention is meant to include all such isomers of these compounds. Independent synthesis of these diastereomers or their chromatographic separation can be accomplished as known in the art by appropriate modification of the methodology disclosed herein. These absolute stereochemistry can be determined by X-ray crystallographic analysis of crystalline products or derived crystal intermediates, if necessary, using reagents containing known asymmetric centers of absolute configuration. it can. If desired, racemic mixtures of the compounds can be separated so that the individual enantiomers are isolated. Separation is accomplished by methods well known in the art, for example, coupling a racemic mixture of compounds with an enantiomerically pure compound to form a mixture of diastereoisomers, followed by fractional crystallization of the individual diastereomers. Alternatively, it can be carried out by separation by standard methods such as chromatography.

  This is the aryl cyclohexyl ether-head group (HG) of the compound of formula (I), ie:

［式中、少なくとも炭素原子１及び４は、不斉炭素原子であり、そしてＲ^１は、さらに不斉炭素原子を含むこともあり得る］に、特にあてはまる。本発明は頭部基の全ての個々の立体異性体及びそれらの混合物を含むことが理解される。

This is especially true in which at least carbon atoms 1 and 4 are asymmetric carbon atoms, and R ¹ may further contain asymmetric carbon atoms. It is understood that the present invention includes all individual stereoisomers of the head group and mixtures thereof.

  Specifically, the present invention provides compounds of formula (I):

［式中、
Ｒ^１は、アリール又はヘテロアリール（非置換であるか、又はＡより独立に選択される１個以上の置換基で置換されている）であり；
Ｒ^２は、
Ｈ、
Ｃ_１−１２−アルキル（非置換であるか、又は１個以上のＯＨ、ハロ、シアノもしくはＣ_１−１２−アルコキシで置換されている）、
−（ＣＨ_２）_ｑ−Ｒ^ａ（ここで、Ｒ^ａは、各々、非置換であるか、又はＡより独立に選択される１個以上の置換基で置換されている、フェニル又は５員もしくは６員ヘテロアリールである）、
−（ＣＨ_２）_ｒＮＲ^ｉＲ^ｉｉ、
−Ｃ（Ｏ）−Ｃ_１−１２−アルキル（ここで、Ｃ_１−１２−アルキルは、非置換であるか、又は１個以上のＯＨ、ハロ、シアノもしくはＣ_１−１２−アルコキシで置換されている）、
−Ｃ（Ｏ）（ＣＨ_２）_ｑＯＣ（Ｏ）−Ｃ_１−１２−アルキル、
−Ｃ（Ｏ）（ＣＨ_２）_ｑＮＲ^ｉＲ^ｉｉ、
−Ｃ（Ｏ）Ｏ−Ｃ_１−１２−アルキル（ここで、アルキルは、非置換であるか、又は１個以上のＯＨ、ハロ、シアノもしくはＣ_１−１２−アルコキシで置換されている）、
−Ｓ（Ｏ）_２−Ｃ_１−１２−アルキル、
−Ｓ（Ｏ）_２ＮＲ^ｉＲ^ｉｉ（Ｒ^ｉ及びＲ^ｉｉは、各々独立に、Ｈ、Ｃ_１−１２−アルキルであるか、或いは、それらが結合している窒素と一緒になって、Ｎ、Ｏ又はＳより選択される１個又は２個のヘテロ原子を含有する３員〜７員ヘテロシクロアルキルを形成し、該ヘテロシクロアルキルは、非置換であるか、又はＢより独立に選択される１個以上の置換基で置換されている）であり、
ｑは、１、２、３又は４であり、
ｒは、２、３又は４であり、
Ａは、ハロ、シアノ、ＯＨ、Ｃ_１−７−アルキル、ハロ−Ｃ_１−７−アルキル、Ｃ_１−７−アルコキシ、ハロ−Ｃ_１−７−アルコキシ、又はヒドロキシ−Ｃ_１−７−アルキルであり、
Ｂは、オキソ、ハロ、ＯＨ、Ｃ_１−７−アルキル又はＣ_１−７−アルコキシであり、
Ｒ^３は、Ｃｌ又はＦである］で示される化合物、又はその薬学的に許容しうる塩に関する。

[Where:
R ¹ is aryl or heteroaryl (unsubstituted or substituted with one or more substituents independently selected from A);
R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH, halo, cyano or C _1-12 -alkoxy),
— (CH ₂ ) _q —R ^a, wherein each R ^a is phenyl or 5-membered or unsubstituted or substituted with one or more substituents independently selected from A 6-membered heteroaryl),
_{^{- (CH 2) r NR i}} R ii,
-C (O) _-C1-12 -alkyl, wherein _C1-12 -alkyl is unsubstituted or substituted with one or more OH, halo, cyano or _C1-12 -alkoxy. ing),
_{-C (O) (CH 2)} q OC (O) -C 1-12 - alkyl,
^{_{-C (O) (CH 2)}} q NR i R ii,
-C (O) O- _C1-12 -alkyl, wherein alkyl is unsubstituted or substituted with one or more OH, halo, cyano or _C1-12 -alkoxy.
-S (O) _{2- C1-12} -alkyl,
—S (O) ₂ NR ⁱ R ⁱⁱ (R ⁱ and R ⁱⁱ are each independently H, C _1-12 -alkyl, or together with the nitrogen to which they are attached, N Forms a 3- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from, O or S, wherein the heterocycloalkyl is unsubstituted or independently selected from B Substituted with one or more substituents)
q is 1, 2, 3 or 4;
r is 2, 3 or 4;
A is halo, cyano, OH, C _1-7 -alkyl, halo-C _1-7 -alkyl, C _1-7 -alkoxy, halo-C _1-7 -alkoxy, or hydroxy-C _1-7 -alkyl And
B is oxo, halo, OH, C _1-7 -alkyl or C _1-7 -alkoxy,
R ³ is Cl or F], or a pharmaceutically acceptable salt thereof.

  In particular, these head groups, HG, are:

である。

It is.

  Further, it is understood that all embodiments of the invention described herein may be combined with one another.

In certain embodiments, A is halo, cyano, OH, C _1-7 -alkyl, halo-C _1-7 -alkyl, C _1-7 -alkoxy, halo-C _1-7 -alkoxy, or hydroxy- C _1-7 -alkyl.

In certain embodiments, A is halo, cyano, C _1-7 -alkyl, halo-C _1-7 -alkyl, or C _1-7 -alkoxy.

In certain embodiments, R ¹ is aryl or heteroaryl (which is unsubstituted or substituted with one or more substituents independently selected from A); and A is It is synonymous.

In certain embodiments, R ¹ is a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring, or a ring heteroatom selected from N, O, or S Is a monovalent 5-membered or 6-membered monocyclic aromatic ring, or 9-membered or 10-membered bicyclic aromatic ring, wherein the remaining ring atom is C, Is substituted or substituted with one or more substituents independently selected from A; and A is as defined above.

In certain embodiments, R ¹ is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from A And A is as defined above.

In certain embodiments, R ¹ is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl (each unsubstituted or independently from methyl, t-butyl, Cl, F, trifluoromethyl, methoxy or cyano) Substituted with one or more substituents selected from

In certain embodiments, R ¹ is a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic aromatic ring.

In certain embodiments, R ¹ is naphthyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl.

In certain embodiments, R ¹ is phenyl or pyridinyl.

In certain embodiments, R ¹ is phenyl, 4-fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl-phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3 -Methyl-phenyl, 3-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2-cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro-phenyl, naphtho 2-yl, naphth-1-yl, pyridin-3-yl, 5-chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 3-fluoro-pyridin-2 -Yl, 5-fluoro-pyridin-2-yl, 6-methyl-pyridin-2-yl, 2,6-di-methyl-pyrimidin-4-yl, pyrimidine-2 -Yl, pyrazin-2-yl, pyridin-4-yl or pyridazin-3-yl.

In certain embodiments, R ¹ is phenyl, 4-fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl-phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3 -Methyl-phenyl, 3-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2-cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro-phenyl, naphtho 2-yl, naphth-1-yl, pyridin-3-yl, 5-chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 2,6-di-methyl -Pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridin-4-yl or pyridazin-3-yl.

In certain embodiments, R ² is as described above.

In certain embodiments, R ² is H. Thus, free bases or inorganic or organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid Etc. to form any of the pharmaceutically acceptable acid addition salts.

In certain embodiments, R ² is C _1-12 -alkyl (unsubstituted or substituted with one or more OH, halo, cyano, or C _1-12 -alkoxy). In certain embodiments, R ² is C _1-12 -alkyl (unsubstituted or substituted with one or more OH).

In certain embodiments, R ² is — (CH ₂ ) _q —R ^a , wherein each R ^a is one or more substitutions that are unsubstituted or independently selected from A Is substituted with a group phenyl or 5- or 6-membered heteroaryl and A is as defined above and q is 1, 2, 3 or 4, preferably 1. In certain embodiments, R ² is — (CH ₂ ) _q —R ^a , wherein each R ^a is one or more substitutions that are unsubstituted or independently selected from A Phenyl or 5- or 6-membered heteroaryl substituted with a group and A is halo, cyano, OH, C _1-7 -alkyl, halo-C _1-7 -alkyl, or C _1-7 -Alkoxy; and q is 1, 2, 3 or 4, preferably 1. In certain embodiments, R ² is — (CH ₂ ) _q —R ^a , where R ^a is phenyl or 5- or 6-membered heteroaryl, and q is 1, 2, 3 Or 4, preferably 1. In certain embodiments, ^{R 2,} -CH ₂ - pyridinyl or benzyl, preferably -CH ₂ - pyridin-2-yl.

In certain embodiments, R ² is —C (O) —C _1-12 -alkyl, wherein alkyl is unsubstituted or one or more OH, halo, cyano, or C _1. Substituted with _-12 -alkoxy. In certain embodiments, R ² is —C (O) —C _1-12 -alkyl.

In certain embodiments, R ² is —C (O) (CH ₂ ) _q NR ⁱ R ⁱⁱ , wherein q is 1, 2, 3 or 4, preferably 1, wherein R ⁱ and R ⁱⁱ are each independently H, C _1-12 -alkyl, or together with the nitrogen to which they are attached, one or two selected from N, O or S Forming a 3 to 7 membered heterocycloalkyl containing heteroatoms, which is unsubstituted or substituted with one or more substituents independently selected from B And B is oxo, halo, OH, C _1-7 -alkyl or C _1-7 -alkoxy. In certain embodiments, R ² is C (O) (CH ₂ ) _q NR ⁱ R ⁱⁱ , where q is 1, 2, 3 or 4, preferably 1, and R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _1-12 -alkyl.

In certain embodiments, R ² is —C (O) O—C _1-12 -alkyl, wherein alkyl is unsubstituted or one or more OH, halo, cyano, or C Substituted with _1-12 -alkoxy. In certain embodiments, R ² is —C (O) O—C _1-12 -alkyl.

In certain embodiments, R ² is —S (O) ₂ —C _1-12 -alkyl.

In certain embodiments, R ² is —S (O) ₂ NR ⁱ R ⁱⁱ , wherein R ⁱ and R ⁱⁱ are each independently H, C _1-12 -alkyl, or Together with the nitrogen to which they are attached, a 3- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S is formed, wherein the heterocycloalkyl is , Unsubstituted or substituted with one or more substituents independently selected from B, and B is oxo, halo, OH, C _1-7 -alkyl or C _1-7 -alkoxy It is. In certain embodiments, R ² is —S (O) ₂ NR ⁱ R ⁱⁱ , wherein R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _{1. It is -12} -alkyl.

In certain embodiments, R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH or F),
^{_{- (CH 2) q -R a}} ( where, ^{R a} is phenyl or 5- or 6-membered heteroaryl, and, q is 1, 2, 3 or 4, preferably 1),
-C (O) _-C1-12 -alkyl,
—C (O) (CH ₂ ) _q NR ⁱ R ^ii, where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _1-12 -alkyl, and q is 1, 2, 3, or 4, preferably 1,)
-C (O) O- _C1-12 -alkyl,
—S (O) ₂ —C _1-12 -alkyl, or —S (O) ₂ NR ⁱ R ⁱⁱ (where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably Is C _1-12 -alkyl).

In certain embodiments, R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH),
^{_{- (CH 2) q -R a}} ( where, ^{R a} is phenyl or 5- or 6-membered heteroaryl, and, q is 1, 2, 3 or 4, preferably 1),
-C (O) _-C1-12 -alkyl,
—C (O) (CH ₂ ) _q NR ⁱ R ^ii, where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _1-12 -alkyl, and q is 1, 2, 3 or 4, preferably 1),
-C (O) O- _C1-12 -alkyl,
—S (O) ₂ —C _1-12 -alkyl, or —S (O) ₂ NR ⁱ R ⁱⁱ (where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably Is C _1-12 -alkyl).

In certain embodiments, R ² is 2-hydroxy-ethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, —C (O) CH ₂ N (Me) ₂ , —C (O) methyl, -CH ₂ - pyridin-2-yl, -COO-t-butyl, H, i-propyl, _2-methyl, -S _{(O) 2} methyl or -S _(O) 2 N _(methyl).

In certain embodiments, R ² is 2-hydroxy-ethyl, —C (O) CH ₂ N (Me) ₂ , —C (O) methyl, —CH ₂ -pyridin-2-yl, —COO-t. - butyl, H, i-propyl, _2-methyl, -S _{(O) 2} methyl or -S _(O) 2 N _(methyl).

In certain embodiments, R ³ is Cl or F. In certain embodiments, R ³ is Cl.

  In a particular embodiment of the invention, the formula (I):

［式中、
Ｒ^１は、単環式もしくは二環式芳香族環からなる、一価の環式芳香族炭化水素部分であるか、Ｎ、Ｏ、もしくはＳから選択される環ヘテロ原子を１〜４個含有し、残りの環原子がＣである、一価の５員もしくは６員単環式芳香族環、又は９員もしくは１０員二環式芳香族環であり、各々、非置換であるか、又はＡより独立に選択される１個以上の置換基で置換されており；
Ｒ^２は、
Ｈ、
Ｃ_１−１２−アルキル（非置換であるか、又は１個以上のＯＨで置換されている）、
−（ＣＨ_２）_ｑ−Ｒ^ａ（ここで、Ｒ^ａは、フェニル又は５員もしくは６員ヘテロアリールであり、そしてｑは、１、２、３又は４、好ましくは１である）、
−Ｃ（Ｏ）−Ｃ_１−１２−アルキル、
−Ｃ（Ｏ）（ＣＨ_２）_ｑＮＲ^ｉＲ^ｉｉ（ここで、Ｒ^ｉ及びＲ^ｉｉは、各々独立に、Ｈ又はＣ_１−１２−アルキル、好ましくはＣ_１−１２−アルキルであり、そしてｑは、１、２、３又は４、好ましくは１である）、
−Ｃ（Ｏ）Ｏ−Ｃ_１−１２−アルキル、
−Ｓ（Ｏ）_２−Ｃ_１−１２−アルキル、又は
−Ｓ（Ｏ）_２ＮＲ^ｉＲ^ｉｉ（式中、Ｒ^ｉ及びＲ^ｉｉは、各々独立に、Ｈ又はＣ_１−１２−アルキル、好ましくはＣ_１−１２−アルキルである）であり、
Ｒ^３は、Ｃｌ又はＦであり、
Ａは、ハロ、シアノ、ＯＨ、Ｃ_１−７−アルキル、ハロ−Ｃ_１−７−アルキル、又はＣ_１−７−アルコキシである］で示される化合物、又はその薬学的に許容しうる塩が提供される。

[Where:
R ¹ is a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring, or contains 1 to 4 ring heteroatoms selected from N, O, or S And the remaining ring atom is C, a monovalent 5-membered or 6-membered monocyclic aromatic ring, or a 9-membered or 10-membered bicyclic aromatic ring, each being unsubstituted, or Substituted with one or more substituents independently selected from A;
R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH),
^{_{- (CH 2) q -R a}} ( where, ^{R a} is phenyl or 5- or 6-membered heteroaryl and q is 1, 2, 3 or 4, preferably 1),
-C (O) _-C1-12 -alkyl,
—C (O) (CH ₂ ) _q NR ⁱ R ^ii, where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _1-12 -alkyl, and q is 1, 2, 3 or 4, preferably 1),
-C (O) O- _C1-12 -alkyl,
-S _{(O) 2 -C 1-12} - in the alkyl, or _{^{-S (O) 2 NR i R}} ii ( wherein, ^{R i} and ^{R ii} are each independently, H, or _{C 1-12} - alkyl, preferably Is C _1-12 -alkyl),
R ³ is Cl or F;
A is halo, cyano, OH, C _1-7 -alkyl, halo-C _1-7 -alkyl, or C _1-7 -alkoxy], or a pharmaceutically acceptable salt thereof. Provided.

  In a particular embodiment of the invention, the compound of formula (I) has the formula (I '):

［式中、
ＨＧは、下記：

[Where:
HG is:

より選択され、そして
Ｒ^１、Ｒ^２及びＲ^３は、上記のとおりであり、それらの全ての組み合わせを含む］で示される、サブセットとして提供される。

And R ¹ , R ² and R ³ are as described above, including all combinations thereof, and are provided as a subset.

  Examples for the compounds of the invention are shown in the test part and table below.

Preferred compounds of the invention are shown in the examples. Particularly preferred are:
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride,
trans-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanone,
trans-8-chloro-5-methanesulfonyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-2- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanol,
trans-8-chloro-5-isopropyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-sulfonic acid dimethylamide,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -2-dimethylamino-ethanone,
trans-8-fluoro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-fluoro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
cis-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
cis-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-Chloro-1- [4- (4-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-4- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy]- Benzonitrile,
trans-8-chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester,
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-3- [4- (8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile,
trans-8-chloro-1- (4-m-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-5-methyl-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester,
trans-8-Chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (2-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-2- [4- (8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride ,
trans-2- [4- (8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile,
trans-8-chloro-1- (4-o-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- (4-o-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- [4- (pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
tert-Butyl trans-8-chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylate ester,
trans-8-Chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene ,
trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride,
trans-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-Chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride salt,
trans-8-chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
cis-8-Chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
cis-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-5- (2,2-difluoro-ethyl) -1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3 5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-5- (2-fluoro-ethyl) -1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5 10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-5-ethyl-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-5-ethyl-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-5-ethyl-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene, or
trans-8-chloro-5-methyl-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene.

More preferred compounds are:
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride,
trans-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanone,
trans-8-chloro-5-methanesulfonyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-2- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanol,
trans-8-chloro-5-isopropyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-sulfonic acid dimethylamide,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -2-dimethylamino-ethanone,
trans-8-fluoro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-fluoro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
cis-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
cis-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-Chloro-1- [4- (4-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-4- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy]- Benzonitrile,
trans-8-chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester,
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride, trans- 8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-3- [4- (8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile,
trans-8-chloro-1- (4-m-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-5-methyl-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester,
trans-8-Chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (2-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-2- [4- (8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride ,
trans-2- [4- (8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile,
trans-8-chloro-1- (4-o-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- (4-o-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- [4- (pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
tert-Butyl trans-8-chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylate ester,
trans-8-Chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene ,
trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride,
trans-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-Chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride salt,
trans-8-chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Or
trans-8-chloro-5-methyl-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene is there.

  Particularly preferred are trans-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene and trans -8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene.

  Most preferred is trans-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo. Azulene.

  Particular embodiments of the present invention are the compounds described in any of the embodiments, obtainable by the methods described herein.

  Particular embodiments of the present invention are compounds described in any of the embodiments obtained by the methods described herein.

  Particular embodiments of the present invention are compounds described in any of the embodiments for use as therapeutically active substances.

  Specific embodiments of the invention include dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism A compound according to any of the embodiments for use in the prevention or treatment of spectrum disorders, schizophrenia and aggressive behavior.

  A particular embodiment of the invention is a pharmaceutical composition comprising a compound as described in any of the embodiments.

  A particular embodiment of the invention is a pharmaceutical composition comprising a compound as described in any of the embodiments, wherein the pharmaceutical composition comprises dysmenorrhea, male or female sexual dysfunction, It is useful for the prevention or treatment of hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive behavior.

  A particular embodiment of the invention is the use of a compound as described in any of the embodiments for the manufacture of a medicament.

  A particular embodiment of the invention is the use of a compound as described in any of the embodiments for the manufacture of a medicament, wherein the medicament is dysmenorrhea, male or female sexual dysfunction It is useful for the prevention or treatment of hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive behavior.

  Specific embodiments of the invention include dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism Use of a compound as described in any of the embodiments for the prevention or treatment of spectrum disorders, schizophrenia and aggressive behavior.

  Specific embodiments of the invention include dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism A method for the therapeutic and / or prophylactic treatment of spectrum disorders, schizophrenia and aggressive behavior, comprising administering to a human or animal a compound as defined in any of the embodiments .

  In a particular embodiment, the compounds of formula (I) of the present invention have the formula (II):

で示される化合物を、式（III）：

A compound represented by formula (III):

で示される化合物と反応させて、式（Ｉ）［式中、Ｒ^１、Ｒ^２及びＲ^３は、式（Ｉ）に関する本明細書に上記と同義である］の化合物を得る工程を含む方法に従って、製造することができる。

And reacting with a compound of formula (I) wherein R ¹ , R ² and R ³ are as defined herein above for formula (I). Can be manufactured according to

  This method is described in more detail in the following general schemes and procedures AG.

  Compounds of formula (I) can be prepared by thermal condensation of a hydrazide derivative of formula (II) and a thiolactam derivative of formula (III). The synthesis of compounds of formula (II) is outlined in the general schemes DG described later herein. Compounds of formula (III) can be prepared according to the general scheme C described later herein. General Scheme A is further described in General Step V later in this specification.

Compounds of formula (I) having an R ² different from H can be obtained from compounds of formula (Ib) (compounds of formula (I) wherein R ² is H) according to methods known in the art, for example of formula (I A compound of Ib), an inorganic base such as a carbonate or an organic base such as a tertiary amine, and an electrophilic reagent R ² -LG where LG is a leaving group such as halogen or sulfonyl , Which are either commercially available or simply prepared according to methods and starting materials known in the art). Alternatively, the compound of formula (I) is replaced with a compound of formula (Ib) such as a ketone or aldehyde and a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. Can be obtained via reductive alkylation by continuous treatment with borohydride derivatives. Compounds of formula (Ib) can be obtained by cleavage of substituent R ² of compounds of formula (I) using methods known in the art. The compound of formula (Ib) is a compound of formula (Ia) (a compound of formula (I) wherein R ² is tert-butoxycarbonyl) in an appropriate solvent, such as methanesulfone in dichloromethane or tetrahydrofuran. It can be conveniently obtained as a salt or free base after workup of a basic aqueous solution by treatment with acid or hydrochloric acid in methanol. General Scheme C is further described in General Steps VI and VII later in this specification.

The thiolactam derivative of formula (III-1) (compound of formula (III) wherein R ² is tert-butoxycarbonyl) can be obtained as follows: of 2-nitrobenzyl alcohol of formula (a) Conversion to the benzyl chloride of formula (b) can be accomplished with a chlorinating reagent such as thionyl chloride in the presence of an organic tertiary amine base. Alkylation of the compound of formula (b) with glycine ethyl ester hydrochloride in the presence of an organic tertiary amine base, and di-tert-butyl dicarbonate of the resulting compound of formula (c) and N-protection with a catalytic amount of 4-N, N-dimethylaminopyridine gives a compound of formula (d). The nitro group can be pretreated with a zinc halide such as zinc bromide and selectively reduced by hydrogenation over palladium on carbon to give an aniline intermediate of formula (e). Cyclization to the lactam of formula (f) is achieved by treatment of the compound of formula (e) with a suitable base, for example potassium tert-butoxide, in tetrahydrofuran. The thiolactam derivative of formula (III-1) is a Lawesson's reagent (2,4-bis- (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetan-2, 4-disulfide) or diphosphorus pentasulfide.

  4-aryloxy-cyclohexane acid ester of formula (VI) under reversal of configuration by etherification of 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) with phenol derivative of formula (V) under Mitsunobu conditions Get. Thus, the trans-4-aryloxy-cyclohexanecarboxylic acid ester of the formula (VI-1) is obtained from the cis-4-hydroxy-cyclohexanecarboxylic acid ester of the formula (IV-1), while the formula (VI- The cis-4-aryloxy-cyclohexanecarboxylic acid ester of 2) is obtained from the trans-4-hydroxy-cyclohexanecarboxylic acid ester of the formula (IV-2).

A compound of formula (VI-a) (a compound of formula (VI) in which R ¹ is heteroaryl) is obtained from a 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) and a heteroaryl chloride of formula (VII): A catalyst system produced at 120 ° C. in the presence of a catalytic or stoichiometric amount of sodium methanesulfinate and potassium carbonate in DMF, or from cuprous iodide and 1,10-phenanthroline, and It can be prepared at reflux temperature in the presence of a base such as cesium carbonate in toluene.

式（VI-b）の化合物（Ｒ^１がＣｌで置換されている、式（VI）の化合物）は、水素化分解条件下、パラジウム担持炭及び酢酸エチル中のトリエチルアミンの存在下で、室温にて脱塩素化することができる。

The compound of formula (VI-b) (compound of formula (VI) in which R ¹ is substituted with Cl) is subjected to hydrogenolysis conditions at room temperature in the presence of palladium on carbon and triethylamine in ethyl acetate. Can be dechlorinated.

  The 4-aryloxy-cyclohexanecarboxylic acid ester of formula (VI) can be converted to the hydrazide derivative of formula (II) by heating with hydrazine hydrate. Alternatively, the ester derivative of formula (VI) is hydrolyzed to the carboxylic acid derivative of formula (VIII) using a biphasic mixture of aqueous sodium hydroxide or potassium hydroxide and an ether solvent such as dioxane. be able to. The hydrazide derivative of formula (II) is obtained by activation of the acid intermediate of formula (VIII) with, for example, ethyl chloroformate, thionyl chloride, oxalyl chloride or peptide coupling reagent and subsequent coupling with hydrazine. Can do.

Corresponding pharmaceutically acceptable salts with acids are prepared by standard methods known to those skilled in the art, e.g. by dissolving the compound of formula (I) in a suitable solvent such as dioxane or THF It can be obtained by adding an amount of the corresponding acid. The product can usually be isolated by filtration or chromatography. Conversion of a compound of formula (I) to a pharmaceutically acceptable salt with a base can be carried out by treating such compound with such a base. One possible way of forming such a salt is, for example, 1 / n equivalent of, for example, M (OH) _n (where M = metal or ammonium cation and n = number of hydroxide anions). To a solution of the compound in a suitable solvent (eg ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and removal of the solvent by evaporation or lyophilization.

  Unless their preparation is described in the examples, the compounds of formula (I), like all intermediate products, can be prepared according to analogous methods or according to the methods described herein. Starting materials are commercially available, known in the art, or can be prepared by methods known in the art or similar.

  It is understood that the compounds of general formula (I) of the present invention can be derivatized at functional groups to provide derivatives that can be converted back to the parent compound in vivo.

Pharmacological Test The compounds of the present invention exhibit V1a activity. These are selective inhibitors of the V1a receptor and are therefore unlikely to cause adverse off-target related side effects. V1a activity can be detected by the method described below.

  Human V1a receptor was cloned from human liver total RNA by RT-PCR. The coding sequence was subcloned in an expression vector after sequencing to confirm the identity of the amplified sequence. In order to show the affinity of the compounds according to the invention for the human V1a receptor, binding studies were carried out. Cell membranes were prepared from HEK293 cells transiently transfected with an expression vector and cultured in a 20 liter fermentor using the following protocol.

  50 g of cells, 30 ml of freshly prepared ice-cold lysis buffer (pH = 7.4, complete cocktail of 50 mM HEPES, 1 mM EDTA, 10 mM magnesium dichloride + protease inhibitor (Roche Diagnostics)) Resuspend in Homogenize with Polytron for 1 minute and sonicate on ice at 80% intensity for 2 x 2 minutes (Vibracell sonicator). The preparation is centrifuged at 500 g for 20 minutes at 4 ° C., the pellet is discarded, and the supernatant is centrifuged for 1 hour at 43,000 g at 4 ° C. (19,000 rpm). The pellet is resuspended in 12.5 ml lysis buffer + 12.5 ml 20% sucrose and homogenized for 1-2 minutes using polytron. Protein concentration is measured by the Bradford method and aliquots are stored at -80 ° C until use. For binding testing, 60 mg of yttrium silicate SPA beads (Amersham) are mixed with a membrane aliquot in binding buffer (50 mM Tris, 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 10 mM magnesium chloride) for 15 minutes with mixing. To do. Next, 50 μl of the bead / membrane mixture is added to each well of the 96-well plate, followed by 50 μl of 4 nM 3H-vasopressin (American Radiolabeled Chemicals). For total binding measurements, 100 μl of binding buffer is added to each well, for non-specific binding, 100 μl of 8.4 mM cold vasopressin, and for compound testing, serial dilutions of each compound in 2% dimethyl sulfoxide. Add 100 μl. Plates are incubated at room temperature for 1 hour, centrifuged at 1000 g for 1 minute, and counted on a Packard Top-Count. Nonspecific binding counts are subtracted from each well and the data is normalized to the maximum specific binding set at 100%. In order to calculate IC50, a curve is fitted using a nonlinear regression model (XLfit), and Ki is calculated using the Cheng-Prussoff equation.

  The following representative data shows the antagonist activity of the compounds according to the invention against the human V1a receptor.

Pharmaceutical compositions The compounds of formula (I) and their pharmaceutically usable acid addition salts can be used as medicaments, eg in the form of pharmaceutical preparations. The pharmaceutical preparation can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

  The compounds of formula (I) and the pharmaceutically usable acid addition salts thereof are pharmaceutically inert, inorganic or organic excipients for the production of tablets, coatings, dragees and hard gelatine capsules. Can be processed together. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such excipients, for example for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like.

  Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

  In addition, the pharmaceutical formulation contains preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for altering osmotic pressure, buffers, masking agents or antioxidants. be able to. They can also contain still other therapeutically valuable substances.

  The dose can vary within wide limits and must of course be adapted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 10 to 1000 mg per person of a compound of general formula (I) is appropriate, but the above upper limit can be exceeded if necessary.

  The following examples illustrate the invention without limiting it. All temperatures are given in degrees Celsius.

Examples of compositions according to the invention are, but are not limited to:
Example A
Tablets of the following composition are produced in the usual way:

Manufacturing procedure Ingredients 1, 2, 3 and 4 are mixed and granulated with purified water.
2. The granules are dried at 50 ° C.
3. Pass the granules through a suitable milling machine.
4). Ingredient 5 is added, mixed for 3 minutes and compressed on a suitable molding machine.

Example B-1
Capsules of the following composition are produced:

Manufacturing procedure Ingredients 1, 2 and 3 are mixed in a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5 and mix for 3 minutes.
3. Fill into suitable capsules.

  The compound of formula (I), lactose and corn starch are mixed first in a mixer and then in a pulverizer. Return the mixture to the mixer and add talc (and magnesium stearate) to it and mix thoroughly. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

Example B-2
A soft gelatin capsule of the following composition is produced:

Manufacturing Procedure The compound of formula (I) is dissolved in a warm melt of the other ingredients, and the mixture is filled into appropriately sized soft gelatin capsules. Filled soft gelatin capsules are processed according to normal procedures.

Example C
A suppository of the following composition is produced:

Manufacturing Procedure The suppository smelt is dissolved in a glass or steel container, mixed well and cooled to 45 ° C. Thereafter, the finely divided compound of formula (I) is added thereto and stirred until it is completely dispersed. The mixture is poured into an appropriately sized suppository mold and allowed to cool, then the suppository is removed from the mold and individually wrapped with paraffin paper or metal foil.

Example D
An injection with the following composition is produced:

Manufacturing Procedure The compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). Adjust the pH to 5.0 with acetic acid. Adjust the volume to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials using an appropriate excess and sterilized.

Example E
A sachet of the following composition is produced:

Manufacturing Procedure The compound of formula (I) is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and taste additives and filled into sachets.

Examples The following Examples 1-97 are provided for illustration of the invention. They should not be viewed as limiting the scope of the invention, but merely as being representative of the invention.

4-hydroxy-cyclohexanecarboxylic acid ester intermediate of formula (IV) 4- hydroxy-cyclohexanecarboxylic acid ester 1
cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester A solution of cis-4-hydroxy-cyclohexanecarboxylic acid (10.0 g, 69.4 mmol) and a catalytic amount of concentrated sulfuric acid in methanol (700 ml) was heated to reflux overnight. . After cooling to room temperature, the reaction mixture was neutralized by the addition of solid sodium carbonate. The mixture was stirred for 30 minutes, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate (150 ml). The solid was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product (10.3 g, 94%) as a colorless oil that was used in the following step without further purification. MS m / e: 159 (M + H ^< + ^> ).

4-hydroxy-cyclohexanecarboxylic acid ester 2
trans-4-Hydroxy-cyclohexanecarboxylic acid methyl ester The title compound is prepared according to the procedure described for the preparation of cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester instead of cis-4-hydroxy-cyclohexanecarboxylic acid. Using -4-hydroxy-cyclohexanecarboxylic acid, it was obtained as a colorless oil in a yield of 63%. ^{MS (EI) m / e:} 159 (M +, 1%), 140 (M + -H 2 0,45%)

4-Aryloxy-cyclohexanecarboxylic acid intermediate of formula (VI) General procedure I: Etherification under Mitsunobu conditions A solution of triphenylphosphine (1.2 eq) in dry tetrahydrofuran (0.1 M ) Is added diethyl azodicarboxylate (1.2 eq) at 0 ° C. After 20 minutes, a phenol derivative of formula (V) (1.2 eq) and a solution of 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) in tetrahydrofuran (1-3 M) are added successively at 5 ° C. After the addition is complete, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature and stirred for 3-18 hours. The solvent is evaporated and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed once or twice with 1M aqueous sodium hydroxide solution. Extract the aqueous layer with ethyl acetate once or twice. The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography gives the 4-aryloxy-cyclohexanecarboxylic acid ester of formula (VI).

General Procedure II: Sodium Methanesulfinate-Mediated Arylation Solution of 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and heteroaryl chloride derivative (1 eq) in dry N, N-dimethylformamide (1M ), Sodium methanesulfinate (85%, 0.25 to 1 eq) and potassium carbonate (1.5 eq) are added in succession. After the addition is complete, the reaction mixture is stirred at 120 ° C. for 3-18 hours. After cooling to room temperature, the reaction mixture is partitioned between tert-butyl methyl ether and water. The layers are separated and the aqueous layer is extracted once or twice with tert-butyl methyl ether. The combined organic layers are washed once or twice with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography gives the 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VI-a).

General Procedure III: Copper-Catalyzed Arylation To a mixture (2M) of cuprous iodide (0.1 eq), 1,10-phenanthroline (0.2 eq) and heteroaryl chloride derivative (1 eq) in toluene. Add 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and cesium carbonate (2 eq). The reaction mixture is heated to reflux for 20 hours. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate once or twice. The combined organic layers are washed once or twice with 0.5 aqueous hydrogen chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography gives the 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VI-a).

4-Aryloxy-cyclohexanecarboxylic acid ester 1
trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a colorless oil in 23% yield.
Phenol: phenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 234 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 2
cis-4-phenoxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a colorless oil in 54% yield.
Phenol: phenol 4-hydroxy-cyclohexanecarboxylic acid ester: trans-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 234 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 3
trans-4- (4-Fluoro-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a pink oil in 29% yield.
Phenol: 4-fluorophenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 252 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 4
trans-4- (4-Cyano-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 4-hydroxybenzonitrile 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 260 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 5
trans-4- (4-Trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 4-trifluoromethyl-phenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 303 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 6
trans-4- (3-Chloro-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a colorless oil in 38% yield.
Phenol: 3-chlorophenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 268 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 7
trans-4- (3-Methoxy-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a pink oil in 33% yield.
Phenol: 3-methoxyphenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 265 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 8
trans-4- (3-Cyano-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a white solid in 29% yield.
Phenol: 3-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 259 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 9
trans-4-m-Tolyloxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to General Procedure I.
Phenol: 3-methylphenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 248 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 10
trans-4- (3-tert-Butyl-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 3-tert-butylphenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 291 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 11
trans-4- (3-Trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 3-trifluoromethylphenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 302 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 12
trans-4- (2-Fluoro-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 4-fluorophenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester

4-Aryloxy-cyclohexanecarboxylic acid ester 13
trans-4- (2-Cyano-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a pink solid in 34% yield.
Phenol: 2-hydroxybenzonitrile 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 260 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 14
trans-4-o-Tolyloxy-cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a colorless oil in 15% yield.
Phenol: 2-methylphenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 248 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 15
trans-4- (3,5-Difluoro-phenoxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as an off-white solid in 22% yield.
Phenol: 3,5-difluorophenol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester

4-Aryloxy-cyclohexanecarboxylic acid ester 16
trans-4- (Naphthalen-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a yellow solid in 20% yield.
Phenol: 2-naphthol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 284 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 17
trans-4- (Naphthalen-1-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a yellow solid in 20% yield.
Phenol: 1-naphthol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 284 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 18
trans-4- (Pyridin-3-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a white solid in 25% yield.
Phenol: 3-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 236 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 19
trans-4- (5-Chloro-pyridin-3-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as an off-white solid in 29% yield.
Phenol: 3-chloro-5-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 270 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 20
trans-4- (Pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a light red solid in 36% yield.
Phenol: 2-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 236 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 21
trans-4- (6-Chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 6-chloro-pyridin-2-ol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 270 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 22
trans-4- (5-Chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 5-chloro-pyridin-2-ol 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 270 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 23
trans-4- (2,6-Dimethyl-pyrimidin-4-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I as a light yellow oil in 32% yield.
Phenol: 2,4-dimethyl-6-hydroxypyrimidine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 265 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 24
cis / trans-4- (pyrimidin-2-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 2)
The title compound was obtained as a yellow amorphous solid according to general procedure III in 24% yield.
Heteroaryl chloride: 2-chloropyrimidine 4-hydroxy-cyclohexanecarboxylic acid ester: cis / trans-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (2: 1)
MS m / e: 251 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 25
cis / trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1)
The title compound was obtained as a white solid in 15% yield according to General Procedure II.
Heteroaryl chloride: 2-chloropyrazine 4-hydroxy-cyclohexanecarboxylic acid ester: cis / trans-4-hydroxy-cyclohexanecarboxylic acid ethyl ester ester (2: 1)
MS m / e: 251 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 26
cis / trans-4- (6-Chloro-pyrimidin-4-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1)
The title compound was obtained as a colorless oil in 38% yield according to general procedure III.
Heteroaryl chloride: 4,6-dichloropyrimidine 4-hydroxy-cyclohexanecarboxylic acid ester: cis / trans-4-hydroxy-cyclohexanecarboxylic acid ethyl ester ester (2: 1)
MS m / e: 284 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 27
cis / trans-4- (pyrimidin-4-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1)
Cis / trans-4- (6-Chloro-pyrimidin-4-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1) (1.05 g, 3.69 mmol) and triethylamine (0.52 ml) in ethyl acetate (37 ml) To a solution purged with 3.69 mmol) of argon was added 10% palladium on charcoal (0.078 g). The reaction mixture was purged with hydrogen gas and stirred at room temperature for 16 hours under hydrogen gas atmosphere. The catalyst and ammonium salt were removed by filtration over Decalite. The filtrate was concentrated under reduced pressure to give the title compound (0.92 g) as a light yellow oil in quantitative yield.
MS m / e: 251 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 28
cis / trans-4- (6-Chloro-pyridazin-3-yloxy) -cyclohexanecarboxylic acid ethyl ester 1: 1)
The title compound was obtained as a white solid in 39% yield according to General Procedure III.
Heteroaryl chloride: 3,6-dichloropyridazine 4-hydroxy-cyclohexanecarboxylic acid ester: cis / trans-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (2: 1)
MS m / e: 285 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 29
cis / trans-4- (pyridazin-3-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1)
Cis / trans-4- (6-Chloro-pyridazin-3-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1) (1.30 g, 4.57 mmol) and triethylamine (0.64 ml) in ethyl acetate (46 ml) 4.57 mmol) of argon purged solution with 10% palladium on charcoal (0.097 g). The reaction mixture was purged with hydrogen gas and stirred at room temperature for 4 hours under hydrogen gas atmosphere. The catalyst and ammonium salt were removed by filtration over Decalite. The filtrate was concentrated under reduced pressure to give the title compound (1.09 g, 95%) as a light yellow oil. MS m / e: 251 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 30
trans-4- (3-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 3-fluoro-2-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 253 (M ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 31
trans-4- (3-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 5-fluoro-2-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 254 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 32
trans-4- (3-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to general procedure I.
Phenol: 2-hydroxy-6-methylpyridine 4-hydroxy-cyclohexanecarboxylic acid ester: cis-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 250 (M + H ⁺ )

4-Aryloxy-cyclohexanecarboxylic acid ester 33
cis-4- (Pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester The title compound was obtained according to General Procedure I.
Phenol: 2-hydroxypyridine 4-hydroxy-cyclohexanecarboxylic acid ester: trans-4-hydroxy-cyclohexanecarboxylic acid methyl ester MS m / e: 236 (M + H ⁺ )

4-aryloxy-cyclohexanecarboxylic acid intermediate of formula (VIII) 4 -aryloxy-cyclohexanecarboxylic acid 1
cis / trans-4- (pyrimidin-2-yloxy) -cyclohexanecarboxylic acid (1: 2)
To a solution of cis / trans-4- (pyrimidin-2-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 2) (0.35 g, 1.4 mmol) in 1,4-dioxane (7 ml) was added 2 M hydroxylated. Aqueous sodium solution (7.0 ml, 14 mmol) was added. Following 16 hours of stirring at room temperature, it was acidified to pH 2-3 with 0.5 M aqueous hydrogen chloride (50 ml) and extracted three times with 100 ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.26 g, 83%) as a yellow oil.
MS m / e: 221 (M-H ^<+> ).

4-Aryloxy-cyclohexanecarboxylic acid 2
cis / trans-4- (pyrimidin-4-yloxy) -cyclohexanecarboxylic acid (1: 1)
To a solution of cis / trans-4- (pyrimidin-4-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1) (0.90 g, 3.6 mmol) in 1,4-dioxane (18 ml) was added 2M hydroxylated. Aqueous sodium solution (18 ml, 36 mmol) was added. Following 3 hours of stirring at room temperature, it was acidified to pH 2-3 with 1M aqueous hydrogen chloride solution (42 ml) and extracted four times with 100 ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.76 g, 95%) as a white solid.
MS m / e: 221 (M-H ^<+> ).

4-Aryloxy-cyclohexanecarboxylic acid 3
cis / trans-4- (pyridazin-3-yloxy) -cyclohexanecarboxylic acid (1: 1)
To a solution of cis / trans-4- (pyridazin-3-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1) (1.05 g, 4.19 mmol) in 1,4-dioxane (21 ml) was added 2M hydroxylated. Aqueous sodium solution (21 ml, 42 mmol) was added. Following 16 hours of stirring at room temperature, it was acidified to pH 2-3 with 1M aqueous hydrogen chloride solution (44 ml) and extracted three times with 100 ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.80 g, 86%) as an off-white solid.
MS m / e: 221 (M-H ^<+> ).

Hydrazide intermediate of formula (II) General procedure IV: Conversion of ester to hydrazide 4- (aryloxy) -cyclohexanecarboxylic acid ester of formula (VI) (1 eq) and hydrazine hydrate (5 eq) And the mixture is heated at 120 ° C. for 5 hours. After cooling to room temperature, the reaction mixture is partitioned between dichloromethane and water. The layers are separated and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound which is used in the next step without further purification.

Hydrazide 1
trans-4-phenoxy-cyclohexanecarboxylic acid hydrazide
A mixture of trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester (1.07 g, 4.57 mmol) and hydrazine hydrate (0.22 g, 4.48 mmol) was heated at 120 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give the crude title compound as a white solid in quantitative yield, which was used in the next step without further purification.
MS m / e: 235 (M + H ^< + ^> )

Hydrazide 2
cis-4-phenoxy-cyclohexanecarboxylic acid hydrazide
A mixture of cis-4-phenoxy-cyclohexanecarboxylic acid methyl ester (0.55 g, 2.3 mmol) and hydrazine hydrate (0.11 g, 2.3 mmol) was heated at 120 ° C. for 24 hours. After cooling to room temperature, the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was resuspended in toluene (70 ml). The solvent was evaporated and the residue was dried under high vacuum (1-2 mbar) to give the crude title compound (0.50 g, 92%) as a light yellow foam which was further purified without further purification. Used in the process.
MS m / e: 235 (M + H ^< + ^> )

Hydrazide 3
trans-4- (4-Fluoro-phenoxy) -cyclohexanecarboxylic acid hydrazide
A mixture of trans-4- (4-fluoro-phenoxy) -cyclohexanecarboxylic acid methyl ester (0.23 g, 0.93 mmol) and hydrazine hydrate (0.046 g, 0.91 mmol) was added at 120 ° C. to 3.5. Heated for hours. After cooling to room temperature, the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was resuspended in toluene (70 ml). The solvent was evaporated and the residue was dried under high vacuum (1-2 mbar) to give the crude title compound (0.22 g, 96%) as a white solid that was not further purified in the next step. used. MS m / e: 253 (M + H ⁺ )

Hydrazide 4
trans-4- (4-Cyano-phenoxy) -cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4- (4-cyano-phenoxy) -cyclohexanecarboxylic acid methyl ester according to general procedure IV. MS m / e: 260 (M + H ⁺ )

Hydrazide 5
trans-4- (4-Trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4- (4-trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid methyl ester according to General Procedure IV. MS m / e: 303 (M + H ⁺ )

Hydrazide 6
trans-4- (3-Chloro-phenoxy) -cyclohexanecarboxylic acid hydrazide
A mixture of trans-4- (3-chloro-phenoxy) -cyclohexanecarboxylic acid methyl ester (0.25 g, 0.93 mmol) and hydrazine hydrate (0.044 ml, 0.91 mmol) was heated at 120 ° C. for 22 hours. did. Additional hydrazine hydrate (0.020 ml, 0.42 mmol) was added followed by stirring at 120 ° C. for 5 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted once with 50 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.21 g, 86%) as a white solid that was used in the next step without further purification. . MS m / e: 269 (M + H ^< + ^> )

Hydrazide 7
trans-4- (3-Methoxy-phenoxy) -cyclohexanecarboxylic acid hydrazide
A mixture of trans-4- (3-methoxy-phenoxy) -cyclohexanecarboxylic acid methyl ester (0.20 g, 0.75 mmol) and hydrazine hydrate (0.035 ml, 0.73 mmol) was heated at 120 ° C. for 22 hours. did. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.18 g, 92%) as a white solid that was used in the next step without further purification. did.
MS m / e: 265 (M + H ⁺ )

Hydrazide 8
trans-4- (3-Cyano-phenoxy) -cyclohexanecarboxylic acid hydrazide trans-4- (3-cyano-phenoxy) -cyclohexanecarboxylic acid methyl ester (0.277 g, 1. 07 mmol) and hydrazine hydrate (0.104 ml, 2.14 mmol) were heated at 120 ° C. for 18 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted once with 50 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with methanol (7 ml). The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give the crude title compound (0.15 g, 55%) as a light red solid that was used in the next step without further purification. MS m / e: 260 (M + H ⁺ )

Hydrazide 9
trans-4-m-Tolyloxy-cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4-m-tolyloxy-cyclohexanecarboxylic acid methyl ester according to General Procedure IV. MS m / e: 249 (M + H ⁺ )

Hydrazide 10
trans-4- (3-tert-butyl-phenoxy) -cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4- (3-tert-butyl-phenoxy) -cyclohexanecarboxylic acid methyl ester according to general procedure IV.

Hydrazide 11
trans-4- (3-Trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4- (3-trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid methyl ester according to General Procedure IV. MS m / e: 303 (M + H ⁺ )

Hydrazide 12
trans-4- (2-Fluoro-phenoxy) -cyclohexanecarboxylic acid hydrazide The title compound was obtained from trans-4- (2-fluoro-phenoxy) -cyclohexanecarboxylic acid methyl ester according to General Procedure IV.

Hydrazide 13
trans-4- (2-Cyano-phenoxy) -cyclohexanecarboxylic acid hydrazide trans-4- (2-cyano-phenoxy) -cyclohexanecarboxylic acid methyl ester (0.20 g, 0. 0) in n-butanol (0.5 ml). 77 mmol) and hydrazine hydrate (0.037 ml, 0.76 mmol) were heated at 120 ° C. for 22 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.18 g, 90%) as a white solid that was used in the next step without further purification. did. MS m / e: 260 (M + H ⁺ )

Hydrazide 14
trans-4-o-Tolyloxy-cyclohexanecarboxylic acid hydrazide
A mixture of trans-4-o-tolyloxy-cyclohexanecarboxylic acid methyl ester (0.091 g, 0.36 mmol) and hydrazine hydrate (0.02 ml, 0.36 mmol) was heated at 120 ° C. for 22 hours. After cooling to room temperature, the reaction mixture was suspended in toluene. After evaporation of the solvent, the residue was dried under high vacuum (1-2 mbar) to give the crude title compound (0.73 g, 81%) as a white solid that was further purified without further purification. Used in. MS m / e: 249 (M + H ⁺ )

Hydrazide 15
trans-4- (3,5-Difluoro-phenoxy) -cyclohexanecarboxylic acid hydrazide
A mixture of trans-4- (3,5-difluoro-phenoxy) -cyclohexanecarboxylic acid methyl ester (0.148 g, 0.548 mmol) and hydrazine hydrate (0.106 ml, 2.19 mmol) Heated for hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The aqueous layer was extracted once with ethyl acetate (50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.14 g, 96%) as a light yellow solid that was not further purified in the next step. used. MS m / e: 271 (M + H ⁺ )

Hydrazide 16
trans-4- (Naphthalen-2-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (Naphthalen-2-yloxy) -cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) in methanol (0.5 ml) And a mixture of hydrazine hydrate (0.02 ml, 0.45 mmol) was heated at 80 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.112 g, 86%) as a yellow solid that was not purified further in the next step. used. MS m / e: 285 (M + H ⁺ )

Hydrazide 17
trans-4- (Naphthalen-1-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (Naphthalen-1-yloxy) -cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) in methanol (0.5 ml) And a mixture of hydrazine hydrate (0.022 ml, 0.45 mmol) was heated at 80 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a 3: 1 mixture of the crude title compound and starting material. This mixture (0.12 g) and hydrazine hydrate (0.022 ml, 0.45 mmol) were dissolved in 1,4-dioxane (0.4 ml) and heated to reflux for 18 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.120 g, 83%) as a yellow solid having a purity of 90%, which was not further purified. Used in the next step. MS m / e: 285 (M + H ⁺ )

Hydrazide 18
trans-4- (Pyridin-3-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (Pyridin-3-yloxy) -cyclohexanecarboxylic acid methyl ester (0.141 g, 0. 1) in n-butanol (0.5 ml). 599 mmol) and hydrazine hydrate (0.029 ml, 0.59 mmol) were heated at 120 ° C. for 22 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.061 g, 43%) as a white solid, which was used in the next step without further purification. did. MS m / e: 236 (M + H ^< + ^> )

Hydrazide 19
trans-4- (5-Chloro-pyridin-3-yloxy) -cyclohexanecarboxylic acid hydrazide methyl trans-4- (5-chloro-pyridin-3-yloxy) -cyclohexanecarboxylate in n-butanol (0.5 ml) A mixture of ester (0.19 g, 0.70 mmol) and hydrazine hydrate (0.14 ml, 2.8 mmol) was heated at 120 ° C. for 18 hours. After cooling to room temperature, the reaction mixture was triturated with toluene (100 ml). The product was collected by filtration and dried under reduced pressure to give the crude title compound (0.15 g, 79%) as a white solid that was used in the next step without further purification. MS m / e: 270 (M + H ⁺ )

Hydrazide 20
trans-4- (Pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (Pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester (1.33 g, 5.66 mmol) in n-butanol (1 ml) And a mixture of hydrazine hydrate (0.55 ml, 11 mmol) was heated at 120 ° C. for 68 hours. After cooling to room temperature, the reaction mixture was evaporated and dried under high vacuum (approximately 1-2 mbar) at 100 ° C. for 2 hours to give the crude title compound (1.28 g, 96%) as a white solid, This was used in the next step without further purification. MS m / e: 236 (M + H ^< + ^> )

Hydrazide 21
trans-4- (6-Chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide The title compound is obtained from trans-4- (6-chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester according to general procedure IV. Obtained.
MS m / e: 270 (M + H ⁺ )

Hydrazide 22
trans-4- (5-Chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide The title compound is obtained from trans-4- (5-chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester according to general procedure IV. Obtained.

Hydrazide 23
trans-4- (2,6-Dimethyl-pyrimidin-4-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (2,6-dimethyl-pyrimidin-4-yloxy)-in n-butanol (0.5 ml)- A mixture of cyclohexanecarboxylic acid methyl ester (0.20 g, 0.76 mmol) and hydrazine hydrate (0.15 ml, 3.0 mmol) was heated to reflux overnight. The reaction mixture was evaporated and dried under high vacuum (approximately 1-2 mbar) to give the crude title compound (0.19 g, 95%) as a white solid which was used in the next step without further purification. did. MS m / e: 265 (M + H ⁺ )

Hydrazide 24
cis / trans-4- (pyrimidin-2-yloxy) -cyclohexanecarboxylic acid hydrazide (1: 2)
A solution of cis / trans-4- (pyrimidin-2-yloxy) -cyclohexanecarboxylic acid (1: 2) (0.258 g, 1.16 mmol) and triethylamine (0.162 ml, 1.16 mmol) in THF (6 ml). To the mixture was added ethyl chloroformate (0.111 ml, 1.16 mmol) at 0 ° C. The reaction mixture was stirred for 1 hour. The ammonium salt was removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.116 g, 2.32 mmol) in methanol (10 ml). The reaction mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate (50 ml) and mixture (1: 1 mixture of 1M aqueous sodium hydroxide and brine) (50 ml). The layers were separated. The aqueous layer was extracted 5 times with 50 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.177 g, 65%) as a white solid that was used in the next step without further purification. did.
MS m / e: 237 (M + H ⁺ )

Hydrazide 25
trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylic acid hydrazide
A mixture of cis / trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylic acid ethyl ester (1.11 g, 4.41 mmol) and hydrazine hydrate (0442 g, 8.83 mmol) was heated at 120 ° C. for 72 hours. did. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude cis / trans-hydrazide was triturated with ethyl acetate (5 ml). The precipitate was collected by filtration and dried under reduced pressure to give the crude title compound (0.236 g, 23%) as a white solid that was used in the next step without further purification. MS m / e: 237 (M + H ⁺ )

Hydrazide 26
cis / trans-4- (pyrimidin-4-yloxy) -cyclohexanecarboxylic acid hydrazide (1: 1)
A solution of cis / trans-4- (pyrimidin-4-yloxy) -cyclohexanecarboxylic acid (1: 1) (0.750 g, 3.37 mmol) and triethylamine (0.470 ml, 3.37 mmol) in THF (16 ml). To the mixture was added ethyl chloroformate (0.322 ml, 3.37 mmol) at 0 ° C. The reaction mixture was stirred for 1 hour. The ammonium salt was removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.338 g, 6.75 mmol) in methanol (20 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and a 1: 1 mixture of 1M aqueous sodium hydroxide solution and brine (30 ml). The organic layer was separated. The aqueous layer was extracted with three 100 ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.588 g, 74%) as an off-white solid that was used in the next step without further purification. did. MS m / e: 237 (M + H ⁺ )

Hydrazide 27cis / trans-4- (pyridazin-3-yloxy) -cyclohexanecarboxylic acid hydrazide (1: 1)
A solution of cis / trans-4- (pyridazin-3-yloxy) -cyclohexanecarboxylic acid (1: 1) (0.780 g, 3.51 mmol) and triethylamine (0.489 ml, 3.37 mmol) in THF (17 ml). To the mixture was added ethyl chloroformate (0.334 ml, 3.51 mmol) at 0 ° C. The reaction mixture was stirred for 1 hour. The ammonium salt was removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.351 g, 7.02 mmol) in methanol (20 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and a 1: 1 mixture of 1M aqueous sodium hydroxide and brine (30 ml). The organic layer was separated. The aqueous layer was extracted 5 times with 75 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.580 g, 70%) as an off-white solid that was used in the next step without further purification. did. MS m / e: 237 (M + H ⁺ )

Hydrazide 28
trans-4- (3-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (3-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester in n-butanol (1 ml) ( A mixture of 0.60 g, 2.4 mmol) and hydrazine hydrate (0.53 ml, 11 mmol) was heated at 125 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane (75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.45 g, 83%) as a white solid. This was used in the next step without further purification. MS m / e: 254 (M + H ⁺ )

Hydrazide 29
trans-4- (5-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (5-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester in n-butanol (1 ml) A mixture of 0.92 g, 3.6 mmol) and hydrazine hydrate (0.80 ml, 16 mmol) was heated at 125 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane (75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.55 g, 67%) as a white solid. This was used in the next step without further purification. MS m / e: 254 (M + H ⁺ )

Hydrazide 30
trans-4- (6-Methyl-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide trans-4- (6-Methyl-pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester in n-butanol (1 ml) ( A mixture of 0.62 g, 2.5 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) was heated at 125 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane (75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.48 g, 86%) as a white solid. This was used in the next step without further purification. MS m / e: 250 (M + H ⁺ )

Hydrazide 31
cis-4- (Pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide cis-4- (Pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester in n-butanol (0.5 ml) (0.39 g, 1. 6 mmol) and hydrazine hydrate (0.40 ml, 8.2 mmol) were heated at 125 ° C. overnight. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane (75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.35 g, 91%) as a colorless oil. This was used in the next step without further purification. MS m / e: 236 (M + H ^< + ^> )

Thiolactam intermediate of formula (III) 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester
a) To a solution of 5-chloro-2-nitrobenzyl alcohol (80 g, 0.42 mol) and triethylamine (64 ml, 0.46 mol ) in 4-chloro-2-chloromethyl-1-nitro-benzene dichloromethane (840 ml) Thionyl chloride (34 ml, 0.46 mol) was added dropwise over 30 minutes while maintaining the internal temperature below 32 ° C. by cooling with a water bath. The reaction mixture was stirred for 3 hours. The solvent was evaporated and the residue was triturated with warm tert-butyl methyl ether (970 ml). The ammonium salt was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (85 g, 99%) as a brown oil that was used in the next step without purification. MS m / e: 205 (M ^<+> ).

b) (5-Chloro-2-nitro-benzylamino) -acetic acid ethyl ester 4-chloro-2-chloromethyl-1-nitro-benzene (85 g, 0.41 mol), glycine ethyl ester hydrochloric acid in ethanol (1000 ml) A mixture of salt (70 g, 0.50 mol) and triethylamine (121.4 ml, 0.8665 mol) was heated to reflux for 8 hours. The solvent was evaporated and the residue was triturated with warm tert-butyl methyl ether. The ammonium salt was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (111 g, 99%) as an amorphous brown solid that was used in the next step without purification. MS m / e: 273 (M + H ^< + ^> )

c) [tert-Butoxycarbonyl- (5-chloro-2-nitro-benzyl) -amino] -acetic acid ethyl ester (5-chloro-2-nitro-benzylamino) -ethyl acetate (110 g, in dichloromethane (1200 ml)) 0.403 mol), di-tert-butyl dicarbonate (180 g, 0.807 mol) and 4-N, N-dimethylaminopyridine (2.51 g, 0.0202 mol) at 0 ° C. for 2 hours. Stir at room temperature for 16 hours. The solvent was evaporated and the crude product was purified by flash chromatography using a mixture of cyclohexane / ethyl acetate as eluent to give the title compound (76.4 g, 51%) as a light yellow viscous oil. MS m / e: 373 (M + H ⁺ )

d) [(2-Amino-5-chloro-benzyl) -tert-butoxycarbonyl-amino] -acetic acid ethyl ester [tert-butoxycarbonyl- (5-chloro-2-nitro-benzyl) in ethyl acetate (1200 ml) Zinc bromide (8.5 g, 0.037 mol) was added to a solution of -amino] -acetic acid ethyl ester (69.0 g, 0.186 mol). The reaction mixture was purged with argon for 15 minutes. After the addition of palladium catalyst (10% supported activated carbon, 7.9 g, 0.0074 mol), the mixture was hydrogenated at atmospheric pressure for approximately 48 hours until approximately 13 L of hydrogen gas had been consumed. The catalyst was removed by filtration and the filtrate was washed twice each with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (60.6 g, 95.5%) as a yellow waxy solid. MS m / e: 343 (M + H ⁺ )

e) 7-Chloro-2-oxo-1,2,3,5-tetrahydro-benzo [1,4] diazepine-4-carboxylic acid tert-butyl ester in (600 ml) [(2-amino-5- Chloro-benzyl) -tert-butoxycarbonyl-amino] -acetic acid ethyl ester (60 g, 0.18 mol) and potassium tert-butoxide (22 g, 0.19 mol) under cooling in an ice-water batch (bacth). Slowly added at 5 ° C. After the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature for 3 hours, followed by the addition of water (400 ml), saturated aqueous ammonium chloride (280 ml) and ethyl acetate (800 ml). After 10 minutes, the precipitate was collected by filtration. The organic layer was separated from the filtrate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was combined with the precipitate (which had previously been collected by filtration) and crystallized from hot ethyl acetate to give the title compound (46 g, 88%) as a white solid.
MS m / e: 295 (M-H ^<+> ).

f) 7-Chloro-2 in 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester tetrahydrofuran (1100 ml) -Oxo-1,2,3,5-tetrahydro-benzo [1,4] diazepine-4-carboxylic acid tert-butyl ester (41.1 g, 0.139 mol) and 2,4-bis- (4-methoxyphenyl) ) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (31.5 g, 0.0763 mol) was heated to reflux for 3 hours. The solvent was evaporated and the residue was triturated with tert-butyl methyl ether. The precipitate was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from hot ethanol to give the title compound (37.5 g, 86.4%) as a light yellow solid.
MS m / e: 311 (M-H &lt; ^{+ &gt;} ).

7-Fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester The title compound is converted to 7-chloro-2-thioxo-1 , 2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester according to the above procedure for the synthesis of 5-chloro-2-nitrobenzyl alcohol in step a) Instead, 5-fluoro-2-nitrobenzyl alcohol was used and obtained as a light yellow solid in equivalent yield. MS m / e: 297 (M-H ^<+> ).

Examples General Procedure V: Condensation of hydrazide and thiolactam to triazoles of hydrazide derivatives of formula (II) (1-1.5 eq) and thiolactams of formula (III) (1 eq) in n-butanol. The mixture (0.1-0.2M) is heated to reflux for 16-72 hours. After cooling to room temperature, the solvent is evaporated and the residue is purified by flash chromatography to give the compound of formula (I). When using a thiolactam of formula (III-1) (compound of formula (III) wherein R ² is tert-butoxycarbonyl), the resulting triazole product of formula (Ia) N-tert- The butoxycarbonyl group may be partially or fully thermally cleaved to give the secondary amine derivative of formula (Ib) as an additional product or a single product.

General Procedure VI: Cleavage of the N-tert-butoxycarbonyl (N-BOC) group of an N-BOC derivative of the general formula (Ia) (1 equivalent) in hydrogen chloride solution of 1.25 M methanol or 1.5 M ethanol The solution (10-20 equivalents of HCl) is heated at 50 ° C. for 15-60 minutes. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure to give the secondary amine derivative of general formula (Ib) as the hydrochloride salt. In some cases, the free base can be obtained by partitioning the hydrochloride salt between 1M aqueous sodium hydroxide and an organic solvent such as ethyl acetate or dichloromethane. The layers are separated and the aqueous layer is extracted twice with an organic solvent. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the free base of the compound of formula (Ib).

General Procedure VII: Reductive N-alkylation of a compound of formula (Ib) as a free base or hydrochloride (1 equivalent, 0.1-0.2 M), triethylamine (a compound of formula (Ib) in methanol When using the hydrochloride salt, a mixture of 1 equivalent) and an aldehyde or ketone (8 equivalents) is heated to reflux for 2-6 hours. After cooling to 0 ° C., sodium cyanoborohydride (2-3 equivalents) is added. The reaction mixture is stirred at room temperature for 3-16 hours and quenched with 1M aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography gives the N-alkyl derivative of formula (I).

Example 1
trans-8-Chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester The title compound is prepared according to general procedure V. Yield 83% as a white foam.
Hydrazide: trans-4-phenoxy-cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert- Butyl ester MS m / e: 495 (M + H ⁺ )

Example 2
trans-8-Chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride The title compound was converted to trans-8-chloro-1- Obtained from (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester as a white solid in 98% yield according to general procedure VI . MS m / e: 395 (M + H ⁺ )

Example 3
trans-8-Chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The title compound was trans-8 Yield as a white solid from -chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII Obtained at 64%. MS m / e: 409 (M + H ⁺ )

Example 4
trans-1- [8-Chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanone trans-8-chloro in dichloromethane -1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.071 g, 0.18 mmol) and triethylamine (0.048 ml, 0 .35 mmol) was added acetyl chloride (0.013 ml, 0.18 mmol) at room temperature. Following 18 hours of stirring, it was partitioned between 1M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted once with 50 ml of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography using n-heptane / ethyl acetate as eluent gave the title compound (0.039 g, 54%) as a white solid.
MS m / e: 437 (M + H ⁺ )

Example 5
trans-8-Chloro-5-methanesulfonyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene trans-8 in dichloromethane (5 ml) -Chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulenate (0.065 g, 0.15 mmol) and triethylamine (0.044 ml) , 0.32 mmol) was added methanesulfonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After 20 hours of stirring, the reaction mixture was transferred directly to a silica gel chromatography column. Elution with n-heptane / ethyl acetate gave the title compound (0.051 g, 72%) as a white solid. MS m / e: 473 (M + H ^< + ^> )

Example 6
trans-2- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanol The title compound was trans-8- Yield 59 as a white solid from chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and glycolaldehyde according to general procedure VII %. MS m / e: 439 (M + H ⁺ )

Example 7
trans-8-chloro-5-isopropyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The title compound was converted to trans-8-chloro- Obtained from 1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and acetone as a white solid in 45% yield according to general procedure VII. It was. MS m / e: 437 (M + H ⁺ )

Example 8
trans-8-Chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-sulfonic acid dimethylamide trans-8 in dichloromethane (2.5 ml) -Chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.062 g, 0.14 mmol) and triethylamine (0.030 ml) , 0.22 mmol) was added N, N-dimethylsulfamoyl chloride (0.023 ml, 0.22 mmol) at room temperature. After 72 hours of stirring, the reaction mixture was transferred directly to a silica gel chromatography column. Elution with n-heptane / ethyl acetate gave the title compound (0.042 g, 58%) as a white solid. MS m / e: 502 (M + H ⁺ )

Example 9
trans-8-Chloro-1- (4-phenoxy-cyclohexyl) -5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene in acetonitrile (1 ml) trans-8-Chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.064 g, 0.15 mmol) and potassium carbonate To a mixture of (0.062 ml, 0.45 mmol) 2- (bromomethyl) pyridine hydrobromic acid (0.040 ml, 0.16 mmol) was added at room temperature. Following stirring at 50 ° C. for 72 hours, it was partitioned between 1M aqueous sodium hydroxide (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by rush chromatography using n-heptane / ethyl acetate as eluent gave the title compound (0.044 g, 63%) as a light brown solid. MS m / e: 486 (M + H ^< + ^> )

Example 10
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -2-dimethylamino-ethanone tetrahydrofuran (2 ml ) -Trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.179 g, 0.41 mmol) To the mixture was added triethylamine (0.058 ml, 0.41 mmol). The suspension was stirred for 10 minutes. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml) followed by N, N-dimethylglycine (0.056 g, 0.54 mmol) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.104 g). , 0.54 mmol). Following 18 hours of stirring at 50 ° C., it was partitioned between water (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted once with 50 ml of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography using n-heptane / ethyl acetate as eluent gave the title compound (0.057 g, 28%) as a white solid.
MS m / e: 480 (M + H ⁺ )

Example 11
trans-8-Fluoro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Obtained according to V as a white solid in 54% yield.
Hydrazide: trans-4-phenoxy-cyclohexanecarboxylic acid hydrazide thiolactam: 7-fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert- Butyl ester MS m / e: 479 (M + H ⁺ )

Example 12
trans-8-Fluoro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound is trans-8-fluoro. Quantitative collection as a light yellow solid from -1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI Obtained at a rate. MS m / e: 379 (M + H ^< + ^> )

Example 13
trans-8-Fluoro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The title compound was converted to trans-8-fluoro- 1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII as a white solid in 63% yield Obtained.
MS m / e: 393 (M + H ⁺ )

Example 14
cis-8-Chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester The title compound is prepared according to general procedure V Obtained in 69% yield as a white solid.
Hydrazide: cis-4-phenoxy-cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert- Butyl ester MS m / e: 495 (M + H ⁺ )

Example 15
cis-8-Chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride The title compound was converted to cis-8-chloro-1- Obtained in quantitative yield as a white solid from (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI . MS m / e: 395 (M + H ⁺ )

Example 16
cis-8-Chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The title compound was converted to cis-8-chloro- 1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde according to general procedure VII as a white solid in 73% yield Obtained. MS m / e: 409 (M + H ⁺ )

Example 17
trans-8-Chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a white solid in 66% yield.
Hydrazide: trans-4- (4-fluoro-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester MS m / e: 513 (M + H ^< + ^> )

Example 18
trans-8-Chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound , Trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester Obtained in quantitative yield as a white solid according to Procedure VI. MS m / e: 413 (M + H ⁺ )

Example 19
trans-8-Chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene From -8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride and paraformaldehyde Obtained as a white solid in 70% yield according to general procedure VII. MS m / e: 427 (M + H ^< + ^> )

Example 20
trans-8-Chloro-1- [4- (4-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to General Procedure V.
Hydrazide: trans-4- (4-cyano-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-Carboxylic acid tert-butyl ester MS m / e: 520 (M + H ⁺ )

Example 21
trans-4- [4- (8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride The title compound was trans-8-chloro-1- [4- (4-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid. Obtained from tert-butyl ester according to General Procedure VI. MS m / e: 420 (M + H ⁺ )

Example 22
trans-4- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy]- Benzonitrile The title compound was trans-4- [4- (8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy. ] Obtained according to general procedure VII from benzonitrile hydrochloride and paraformaldehyde. MS m / e: 434 (M + H ⁺ )

Example 23
trans-8-chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester The title compound was obtained according to general procedure V.
Hydrazide: trans-4- (4-trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] Diazepine-4-carboxylic acid tert-butyl ester MS m / e: 563 (M + H ⁺ )

Example 24
trans-8-Chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The compound was converted to trans-8-chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carbon. Obtained from the acid tert-butyl ester according to General Procedure VI. MS m / e: 463 (M + H ⁺ )

Example 25
trans-8-Chloro-5-methyl-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] Azulene The title compound is trans-8-chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e Obtained from azulene hydrochloride and paraformaldehyde according to General Procedure VII. MS m / e: 477 (M + H ⁺ )

Example 26
trans-8-Chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a white solid in 74% yield.
Hydrazide: trans-4- (3-chloro-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester MS m / e: 529 (M + H ^< + ^> )

Example 27
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride 8-Chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI Obtained in quantitative yield. MS m / e: 429 (M + H ⁺ )

Example 28
trans-8-Chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene General procedure from trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde According to VII, it was obtained as a colorless oil in a yield of 83%. MS m / e: 443 (M + H ^< + ^> )

Example 29
trans-8-Chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a white foam in 75% yield.
Hydrazide: trans-4- (3-methoxy-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester MS m / e: 525.5 (M + H ^< + ^> )

Example 30
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound From trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester Obtained in quantitative yield as a white solid according to Procedure VI. MS m / e: 425 (M + H ⁺ )

Example 31
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene trans-8-Chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride and paraformaldehyde To give a white solid in 43% yield according to general procedure VII. MS m / e: 439 (M + H ⁺ )

Example 32
trans-8-Chloro-1- [4- (3-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester Obtained according to general procedure V as a brown solid in 18% yield (having a purity of approximately 80% by LC-MS).
Hydrazide: trans-4- (3-cyano-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-Carboxylic acid tert-butyl ester MS m / e: 520 (M + H ⁺ )

Example 33
trans-3- [4- (8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride The title compound , Trans-8-chloro-1- [4- (3-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester Obtained as a brown solid in 95% yield according to Procedure VI. MS m / e: 420 (M + H ⁺ )

Example 34
trans-3- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile The compound was converted to trans-3- [4- (8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride. And according to general procedure VII from paraformaldehyde as a yellow solid in 43% yield. MS m / e: 434 (M + H ⁺ )

Example 35
trans-8-Chloro-1- (4-m-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Obtained according to General Procedure V.
Hydrazide: trans-4-m-tolyloxy-cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester MS m / e: 509 (M + H ⁺ )

Example 36
trans-8-Chloro-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound was trans-8 -Obtained according to general procedure VI from 4-chloro-1- (4-m-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester .
MS m / e: 409 (M + H ⁺ )

Example 37
trans-8-chloro-5-methyl-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene According to general procedure VII from -8-chloro-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride and paraformaldehyde Obtained. MS m / e: 423.5 (M + H ^< + ^> )

Example 38
trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester The title compound was obtained according to general procedure V.
Hydrazide: trans-4- (3-tert-butyl-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] Diazepine-4-carboxylic acid tert-butyl ester. MS m / e: 551.5 (M + H ^< + ^> )

Example 39
trans-1- [4- (3-tert-Butyl-phenoxy) -cyclohexyl] -8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The compound is trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxyl. Obtained from the acid tert-butyl ester according to General Procedure VI. MS m / e: 451 (M + H ⁺ )

Example 40
trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] Azulene The title compound is trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e Obtained from azulene hydrochloride and paraformaldehyde according to General Procedure VII. MS m / e: 465 (M + H ⁺ )

Example 41
trans-8-chloro-1- [4- (3-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester The title compound was obtained according to general procedure V.
Hydrazide: trans-4- (3-trifluoromethyl-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] Diazepine-4-carboxylic acid tert-butyl ester MS m / e: 563 (M + H ⁺ )

Example 42
trans-8-Chloro-1- [4- (3-trifluoromethyl-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The compound was converted to trans-8-chloro-1- [4- (3-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carbon. Obtained from the acid tert-butyl ester according to General Procedure VI. MS m / e: 463 (M + H ⁺ )

Example 43
trans-8-Chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to General Procedure V.
Hydrazide: trans-4- (2-fluoro-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester MS m / e: 513 (M + H ^< + ^> )

Example 44
trans-8-Chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound , Trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl Obtained from the ester according to General Procedure VI. MS m / e: 413 (M + H ⁺ )

Example 45
trans-8-Chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound was trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride. And from paraformaldehyde according to general procedure VII. MS m / e: 427.5 (M + H ⁺ )

Example 46
trans-8-Chloro-1- [4- (2-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a white foam in 52% yield.
Hydrazide: trans-4- (2-cyano-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-Carboxylic acid tert-butyl ester MS m / e: 520 (M + H ⁺ )

Example 47
trans-2- [4- (8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride The title compound was converted to tert-butyl trans-8-chloro-1- [4- (2-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylate. Obtained from the ester according to general procedure VI as a white solid in 99% yield. MS m / e: 420 (M + H ⁺ )

Example 48
trans-2- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile The compound was converted to trans-2- [4- (8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy] -benzo. Obtained from nitrile hydrochloride and paraformaldehyde as a white solid in 50% yield according to general procedure VII. MS m / e: 434 (M + H ⁺ )

Example 49
trans-8-Chloro-1- (4-o-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester The title compound was prepared according to the general procedure V To give a yellow solid in 52% yield.
Hydrazide: trans-4-o-tolyloxy-cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester MS m / e: 509 (M + H ⁺ )

Example 50
trans-8-Chloro-1- (4-o-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride The title compound is trans-8-chloro- Quantitatively from 1- (4-o-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI as a light yellow solid Obtained in yield. MS m / e: 409 (M + H ⁺ )

Example 51
trans-8-chloro-5-methyl-1- (4-o-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The title compound was converted to trans-8- Chloro-1- (4-o-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde as a light yellow solid according to general procedure VII Obtained in 72% yield. MS m / e: 423 (M + H ^< + ^> )

Example 52
trans-8-Chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester The compound was obtained according to general procedure V as a light yellow solid in 58% yield.
Hydrazide: trans-4- (3,5-difluoro-phenoxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] Diazepine-4-carboxylic acid tert-butyl ester

Example 53
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride From trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester Obtained in quantitative yield as a white solid according to general procedure VI. MS m / e: 431 (M + H ⁺ )

Example 54
trans-8-Chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene Title compound Trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and para Obtained as a white solid in 39% yield from formaldehyde according to general procedure VII. MS m / e: 445 (M + H ⁺ )

Example 55
trans-8-chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a yellow solid in 78% yield.
Hydrazide: trans-4- (naphthalen-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester MS m / e: 545 (M + H ⁺ )

Example 56
trans-8-Chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride 8-Chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI Obtained as a white solid in quantitative yield. MS m / e: 445 (M + H ⁺ )

Example 57
trans-8-chloro-5-methyl-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene General procedure from trans-8-chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde Obtained according to VII as white foam in 60% yield. MS m / e: 459 (M + H ⁺ )

Example 58
trans-8-chloro-1- [4- (naphthalen-1-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a yellow solid in 73% yield.
Hydrazide: trans-4- (naphthalen-1-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester MS m / e: 545 (M + H ⁺ )

Example 59
trans-8-chloro-1- [4- (naphthalen-1-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The title compound was converted to trans-8- Chloro-1- [4- (naphthalen-1-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI, white As a solid with a yield of 97%. MS m / e: 445 (M + H ⁺ )

Example 60
trans-8-chloro-5-methyl-1- [4- (naphthalen-1-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene General procedure from trans-8-chloro-1- [4- (naphthalen-1-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde Obtained in 73% yield as a white foam according to VII. MS m / e: 459 (M + H ⁺ )

Example 61
trans-8-Chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a white foam in 51% yield.
Hydrazide: trans-4- (pyridin-3-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester. MS m / e: 496 (M + H ⁺ )

Example 62
trans-8-Chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene dihydrochloride Title compound From trans-8-chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester Obtained in quantitative yield as a white solid according to general procedure VI. MS m / e: 396 (M + H ⁺ )

Example 63
trans-8-Chloro-5-methyl-1- [4- (pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene trans-8-Chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene dihydrochloride and para Obtained from formaldehyde as a white solid in 41% yield according to general procedure VII. MS m / e: 410 (M + H ⁺ )

Example 64
tert-Butyl trans-8-chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylate Ester The title compound was obtained according to general procedure V as a white foam in 71% yield.
Hydrazide: trans-4- (5-chloro-pyridin-3-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1, 4] Diazepine-4-carboxylic acid tert-butyl ester. MS m / e: 530 (M + H ⁺ )

Example 65
trans-8-Chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride Title compound Trans-8-chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert Obtained in quantitative yield as a white solid from the butyl ester according to general procedure VI. MS m / e: 430 (M + H ⁺ )

Example 66
trans-8-Chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The title compound was transformed into trans-8-chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene. Obtained from the hydrochloride salt and paraformaldehyde as a white solid in 65% yield according to General Procedure VI. MS m / e: 444 (M + H ⁺ )

Example 67
trans-8-Chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester According to general procedure V, obtained as a white foam in 77% yield.
Hydrazide: trans-4- (pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester. MS m / e: 496 (M + H ⁺ )

Example 68
trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride 8-Chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester according to general procedure VI Obtained as a white solid in quantitative yield. MS m / e: 396 (M + H ⁺ )

Example 69
trans-8-Chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene General procedure from trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride and paraformaldehyde Obtained as a white solid in 41% yield according to VII. MS m / e: 410 (M + H ⁺ )

Example 70
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-Butyl ester The title compound was obtained according to general procedure V.
Hydrazide: trans-4- (6-chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1, 4] Diazepine-4-carboxylic acid tert-butyl ester. MS m / e: 530 (M + H ⁺ )

Example 71
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride Salt The title compound is converted to trans-8-chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene. Obtained from -5-carboxylic acid tert-butyl ester according to general procedure VI. MS m / e: 430 (M + H ⁺ )

Example 72
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. -Obtained from benzo [e] azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m / e: 444 (M + H ⁺ )

Example 73
trans-8-Chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-Butyl ester The title compound was obtained according to general procedure V.
Hydrazide: trans-4- (5-chloro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1, 4] Diazepine-4-carboxylic acid tert-butyl ester MS m / e: 530 (M + H ⁺ )

Example 74
trans-8-Chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride Salt The title compound is trans-8-chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene. Obtained from -5-carboxylic acid tert-butyl ester according to general procedure VI. MS m / e: 430 (M + H ⁺ )

Example 75
trans-8-chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. -Obtained from benzo [e] azulene hydrochloride and paraformaldehyde according to general procedure VII. MS m / e: 444 (M + H ⁺ )

Example 76
trans-8-chloro-1- [4- (2,6-dimethyl-pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert -Butyl ester The title compound was obtained according to general procedure V as a white foam in a yield of 64%.
Hydrazide: trans-4- (2,6-dimethyl-pyrimidin-4-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [ 1,4] diazepine-4-carboxylic acid tert-butyl ester. MS m / e: 525.5 MS (M + H ^< + ^> )

Example 77
trans-8-Chloro-1- [4- (2,6-dimethyl-pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride The title compound was trans-8-chloro-1- [4- (2,6-dimethyl-pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5. Obtained in quantitative yield as white solid from carboxylic acid tert-butyl ester according to general procedure VI. MS m / e: 425 (M + H ⁺ )

Example 78
trans-8-chloro-1- [4- (2,6-dimethyl-pyrimidin-4-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza- Benzoazulene The title compound was trans-8-chloro-1- [4- (2,6-dimethyl-pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b- Obtained from tetraaza-benzoazulen hydrochloride and paraformaldehyde as a white solid in 15% yield according to General Procedure VII. MS m / e: 439 (M + H ⁺ )

Example 79
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester And Example 80
cis-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester And cis-8-chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl The ester was obtained after separation by flash column chromatography according to general procedure V.
Hydrazide: cis / trans-4- (pyrimidin-2-yloxy) -cyclohexanecarboxylic acid hydrazide (1: 2)
Thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Was obtained as an off-white solid in 38% yield.
MS m / e: 497 (M + H ⁺ )
cis-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Was obtained as an off-white solid in 8% yield.
MS m / e: 497 (M + H ⁺ )

Example 81
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene From -8-chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Obtained as a yellow solid in 73% yield according to general procedure VI. MS m / e: 397 (M + H ⁺ )

Example 82
trans-8-Chloro-5-methyl-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene Title The compound is converted to trans-8-chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene and para. Obtained as a white solid in 34% yield from formaldehyde according to general procedure VII. MS m / e: 411 (M + H ⁺ )

Example 83
trans-8-Chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V as a white solid in 70% yield.
Hydrazide: trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine- 4-carboxylic acid tert-butyl ester. MS m / e: 497 (M + H ⁺ )

Example 84
trans-8-Chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene From -8-chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Obtained as a yellow solid in 84% yield according to general procedure VI. MS m / e: 397 (M + H ⁺ )

Example 85
trans-8-Chloro-5-methyl-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound is converted to trans-8-chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene and para. Obtained as a white solid in 45% yield from formaldehyde according to general procedure VII. MS m / e: 411 (M + H ⁺ )

Example 86
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester And Example 87
cis-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester And cis-8-chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl The ester was obtained after separation by flash column chromatography according to general procedure V.
Hydrazide: cis / trans-4- (pyrimidin-4-yloxy) -cyclohexanecarboxylic acid hydrazide (1: 1)
Thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Was obtained as a white solid in 24% yield.
MS m / e: 497 (M + H ⁺ )
cis-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Was obtained according to general procedure V as a white solid in 23% yield.
MS m / e: 497 (M + H ⁺ )

Example 88
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound , Trans-8-chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl Obtained in quantitative yield from the ester according to general procedure VI as an off-white solid. MS m / e: 397 (M + H ⁺ )

Example 89
trans-8-Chloro-5-methyl-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene Title The compound was trans-8-chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride. And from paraformaldehyde according to general procedure VII as a white solid in 29% yield. MS m / e: 411 (M + H ⁺ )

Example 90
cis-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound Cis-8-chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl Obtained in quantitative yield as a white solid from the ester according to general procedure VI. MS m / e: 397 (M + H ⁺ )

Example 91
cis-8-Chloro-5-methyl-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound was converted to cis-8-chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride. And according to general procedure VII from paraformaldehyde as a white solid in 28% yield. MS m / e: 411 (M + H ⁺ )

Example 92
trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester And Example 93
cis-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester
trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester And cis-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl The ester was obtained after separation by flash column chromatography according to general procedure V.
Hydrazide: cis / trans-4- (pyridazin-3-yloxy) -cyclohexanecarboxylic acid hydrazide (1: 1)
Thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine-4-carboxylic acid tert-butyl ester
trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Was obtained as a white solid in 19% yield.
MS m / e: 497 (M + H ⁺ )
cis-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester Was obtained as a white solid in 23% yield.
MS m / e: 497 (M + H ⁺ )

Example 94
trans-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound , Trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl Obtained in quantitative yield from the ester according to general procedure VI as an off-white solid. MS m / e: 397 (M + H ⁺ )

Example 95
trans-8-Chloro-5-methyl-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene Title The compound was converted to trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride. And from paraformaldehyde according to general procedure VII as a white solid in 11% yield. MS m / e: 411 (M + H ⁺ )

Example 96
cis-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride The title compound Cis-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylate tert-butyl Obtained in quantitative yield from the ester according to general procedure VI as an off-white solid. MS m / e: 397 (M + H ⁺ )

Example 97
cis-8-Chloro-5-methyl-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound was converted to cis-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride. And from paraformaldehyde according to general procedure VII as a white solid in 3% yield. MS m / e: 411 (M + H ⁺ )

Example 98
trans-8-Chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound was obtained in 78% yield as a white solid by two steps according to general procedure V followed by treatment of the crude product under the conditions of general procedure VI.
Hydrazide: trans-4- (3-Fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1, 4] diazepine-4-carboxylic acid tert-butyl ester MS m / e: 414 (M + H ⁺ )

Example 99
trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. Obtained as a white solid in 69% yield from benzo [e] azulene and paraformaldehyde according to general procedure VII. MS m / e: 428 (M + H ⁺ )

Example 100
trans-8-Chloro-5-ethyl-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. Obtained as a white solid in 36% yield from benzo [e] azulene and acetaldehyde according to general procedure VII. MS m / e: 442 (M + H ^< + ^> )

Example 101
trans-8-Chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound was obtained in 73% yield as a white solid by two steps according to general procedure V followed by treatment of the crude product under the conditions of general procedure VI.
Hydrazide: trans-4- (5-fluoro-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4 Diazepine-4-carboxylic acid tert-butyl ester MS m / e: 414 (M + H ⁺ )

Example 102
trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. Obtained in 61% yield as a white solid from benzo [e] azulene and paraformaldehyde according to general procedure VII. MS m / e: 428 (M + H ⁺ )

Example 103
trans-8-chloro-5-ethyl-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. Obtained in 76% yield as a colorless waxy solid from benzo [e] azulene and acetaldehyde according to general procedure VII. MS m / e: 442 (M + H ^< + ^> )

Example 104
trans-8-Chloro-5- (2-fluoro-ethyl) -1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5 10b-Tetraaza-benzo [e] azulene trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H in acetonitrile (1.2 ml) A mixture of -2,3,5,10b-tetraaza-benzo [e] azulene (0.10 g, 0.24 mmol) and potassium carbonate (67 mg, 0.48 mmol) was added to 1-bromo-2-fluoroethane (37 mg, 0.29 mmol) at 0 ° C. The cooling bath was removed and the reaction mixture was heated at 70 ° C. overnight. The mixture was filtered and concentrated under reduced pressure. Purification by flash column chromatography gave the title compound (17 mg, 15%) as a white solid. MS m / e: 460 (M + H ⁺ )

Example 105
trans-8-Chloro-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound was obtained in 72% yield as a white solid by two steps according to general procedure V followed by treatment of the crude product under the conditions of general procedure VI.
Hydrazide: trans-4- (6-methyl-pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1, 4] Diazepine-4-carboxylic acid tert-butyl ester MS m / e: 410 (M + H ⁺ )

Example 106
trans-8-chloro-5-methyl-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. Obtained as a white solid in 54% yield from benzo [e] azulene and paraformaldehyde according to general procedure VII. MS m / e: 424 (M + H ⁺ )

Example 107
trans-8-chloro-5-ethyl-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene The title compound was converted to trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza. Obtained in 62% yield as a colorless waxy solid from benzo [e] azulene and acetaldehyde according to general procedure VII. MS m / e: 438 (M + H ⁺ )

Example 108
trans-8-Chloro-5- (2,2-difluoro-ethyl) -1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3 5,10b-Tetraaza-benzo [e] azulene trans-8-chloro-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H in dichloromethane (1 ml) A mixture of -2,3,5,10b-tetraaza-benzo [e] azulene (0.10 g, 0.24 mmol) and N, N-diisopropylethylamine (0.080 ml, 0.49 mmol) was added to trifluoro-methanesulfone. Treated with acid 2,2-difluoro-ethyl ester (63 mg, 0.29 mmol) at 0 ° C. After 30 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was partitioned between aqueous ammonium chloride (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted once with 50 ml of ethyl acetate. The combined organic layers were washed twice with 50 ml each of a 1M aqueous solution of sodium carbonate. Each aqueous layer was extracted once with 50 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography gave the title compound (98 mg, 85%) as a white solid.
MS m / e: 474 (M + H ⁺ )

Example 109
cis-8-Chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester The title compound was obtained according to general procedure V as a light yellow solid in 79% yield.
Hydrazide: cis-4- (pyridin-2-yloxy) -cyclohexanecarboxylic acid hydrazide thiolactam: 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo [e] [1,4] diazepine 4-carboxylic acid tert-butyl ester MS m / e: 496 (M + H ⁺ )

Example 110
cis-8-Chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene -8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester hydrochloride Obtained from the salt and paraformaldehyde as a light yellow solid in 81% yield according to General Procedure VI.
MS m / e: 396 (M + H ⁺ )

Example 111
cis-8-Chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene The compound is converted to cis-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene and para. Obtained as a white solid in 51% yield from formaldehyde according to general procedure VII. MS m / e: 410 (M + H ⁺ )

Claims (26)

Formula (I):

[Where:
R ¹ is aryl or heteroaryl (unsubstituted or substituted with one or more substituents independently selected from A);
R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH, halo, cyano or C _1-12 -alkoxy),
— (CH ₂ ) _q —R ^a, wherein each R ^a is phenyl or 5-membered or unsubstituted or substituted with one or more substituents independently selected from A 6-membered heteroaryl),
_{^{- (CH 2) r NR i}} R ii,
-C (O) _-C1-12 -alkyl, wherein _C1-12 -alkyl is unsubstituted or substituted with one or more OH, halo, cyano or _C1-12 -alkoxy. ing),
_{-C (O) (CH 2)} q OC (O) -C 1-12 - alkyl,
^{_{-C (O) (CH 2)}} q NR i R ii,
-C (O) O- _C1-12 -alkyl, wherein alkyl is unsubstituted or substituted with one or more OH, halo, cyano or _C1-12 -alkoxy.
-S (O) _{2- C1-12} -alkyl,
—S (O) ₂ NR ⁱ R ⁱⁱ (R ⁱ and R ⁱⁱ are each independently H, C _1-12 -alkyl, or together with the nitrogen to which they are attached, N Forms a 3- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from, O or S, wherein the heterocycloalkyl is unsubstituted or independently selected from B Substituted with one or more substituents)
q is 1, 2, 3 or 4;
r is 2, 3 or 4;
A is halo, cyano, OH, C _1-7 -alkyl, halo-C _1-7 -alkyl, C _1-7 -alkoxy, halo-C _1-7 -alkoxy, or hydroxy-C _1-7 -alkyl And
B is oxo, halo, OH, C _1-7 -alkyl or C _1-7 -alkoxy,
R ³ is Cl or F], or a pharmaceutically acceptable salt thereof. R ¹ is
A monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring,
A monovalent 5- or 6-membered monocyclic aromatic ring containing 1 to 4 ring heteroatoms selected from N, O or S, and the remaining ring atoms being C, or 9 or 10 A membered bicyclic aromatic ring,
Each is unsubstituted or substituted with one or more substituents independently selected from A; and A is halo, cyano, OH, C _1-7 -alkyl, halo-C _{1- 7} -alkyl, C _1-7 -alkoxy, halo-C _1-7 -alkoxy, hydroxy-C _1-7 -alkyl,
A compound of formula (I) according to claim 1. R ¹ is a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic aromatic ring, the compounds of formula (I) according to any one of claims 1 or 2. A compound of formula (I) according to any one of claims 1 or 2, wherein R ¹ is naphthyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl. R ¹ is phenyl, 4-fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl-phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3-methyl-phenyl, 3 -T-butyl-phenyl, 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2-cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro-phenyl, naphth-2-yl, naphtho -1-yl, pyridin-3-yl, 5-chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 3-fluoro-pyridin-2-yl, 5-fluoro -Pyridin-2-yl, 6-methyl-pyridin-2-yl, 2,6-di-methyl-pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-y 3. A compound of formula (I) according to any one of claims 1 or 2, which is ru, pyridin-4-yl or pyridazin-3-yl. R ¹ is phenyl, 4-fluoro-phenyl, 4-cyanophenyl, 4-trifluoromethyl-phenyl, 3-chloro-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3-methyl-phenyl, 3 -T-butyl-phenyl, 3-trifluoromethyl-phenyl, 2-fluoro-phenyl, 2-cyano-phenyl, 2-methyl-phenyl, 3,5-di-fluoro-phenyl, naphth-2-yl, naphtho -1-yl, pyridin-3-yl, 5-chloro-pyridin-3-yl, pyridin-2-yl, 6-chloro-pyridin-2-yl, 2,6-di-methyl-pyrimidin-4-yl Or a compound of formula (I) according to any one of claims 1 or 2, which is pyrimidin-2-yl, pyrazin-2-yl, pyridin-4-yl or pyridazin-3-yl. Compound. A compound of formula (I) according to any one of claims 1 to 4, wherein R ¹ is phenyl or pyridinyl. R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH or F),
^{_{- (CH 2) q -R a}} ( where, ^{R a} is phenyl or 5- or 6-membered heteroaryl, and, q is 1, 2, 3 or 4, preferably 1),
-C (O) _-C1-12 -alkyl,
—C (O) (CH ₂ ) _q NR ⁱ R ^ii, where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _1-12 -alkyl, and q is 1, 2, 3, or 4, preferably 1,)
-C (O) O- _C1-12 -alkyl,
—S (O) ₂ —C _1-12 -alkyl, or —S (O) ₂ NR ⁱ R ⁱⁱ (where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably Is C _1-12 -alkyl),
The compound according to any one of claims 1 to 7. R ² is
H,
C _1-12 -alkyl (unsubstituted or substituted with one or more OH),
^{_{- (CH 2) q -R a}} ( where, ^{R a} is phenyl or 5- or 6-membered heteroaryl, and, q is 1, 2, 3 or 4, preferably 1),
-C (O) _-C1-12 -alkyl,
—C (O) (CH ₂ ) _q NR ⁱ R ^ii, where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably C _1-12 -alkyl, and q is 1, 2, 3 or 4, preferably 1),
-C (O) O- _C1-12 -alkyl,
—S (O) ₂ —C _1-12 -alkyl, or —S (O) ₂ NR ⁱ R ⁱⁱ (where R ⁱ and R ⁱⁱ are each independently H or C _1-12 -alkyl, preferably Is C _1-12 -alkyl),
The compound according to any one of claims 1 to 8. R ² _{is, C 1-12} - alkyl, a compound of formula (I) according to any one of claims 1 to 9. R ² is 2-hydroxy-ethyl, 2-fluoro-ethyl, 2,2-difluoro-ethyl, —C (O) CH ₂ N (Me) ₂ , —C (O) methyl, —CH ₂ -pyridine- 11. One of claims 1 to 10, which is 2-yl, —COO-t-butyl, H, i-propyl, methyl, —S (O) ₂ methyl or —S (O) ₂ N (methyl) _2. The compound according to Item. R ² is 2-hydroxy-ethyl, —C (O) CH ₂ N (Me) ₂ , —C (O) methyl, —CH ₂ -pyridin-2-yl, —COO-t-butyl, H, i - propyl, methyl, -S _{(O) 2} methyl or -S _(O) 2 N _{(methyl) 2,} the compound of any one of claims 1 to 11. R ² is methyl, compound of any one of claims 1 to 12. R ³ is Cl, the compound of any one of claims 1 to 13. The compound is:
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride,
trans-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanone,
trans-8-chloro-5-methanesulfonyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-2- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -ethanol,
trans-8-chloro-5-isopropyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-sulfonic acid dimethylamide,
trans-8-chloro-1- (4-phenoxy-cyclohexyl) -5-pyridin-2-ylmethyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-1- [8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulen-5-yl] -2-dimethylamino-ethanone,
trans-8-fluoro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-fluoro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
cis-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
cis-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (4-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-Chloro-1- [4- (4-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-4- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy]- Benzonitrile,
trans-8-chloro-1- [4- (4-trifluoromethyl-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester,
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3-chloro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (3-methoxy-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-3- [4- (8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile,
trans-8-chloro-1- (4-m-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-5-methyl-1- (4-m-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-1- [4- (3-tert-butyl-phenoxy) -cyclohexyl] -8-chloro-4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert- Butyl ester,
trans-8-Chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride,
trans-8-chloro-1- [4- (2-fluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (2-cyano-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-2- [4- (8-Chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -cyclohexyloxy] -benzonitrile hydrochloride ,
trans-2- [4- (8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulen-1-yl) -cyclohexyloxy] -benzonitrile,
trans-8-chloro-1- (4-o-tolyloxy-cyclohexyl) -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- (4-o-tolyloxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-1- [4- (3,5-difluoro-phenoxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- [4- (naphthalen-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-chloro-1- [4- (pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester,
trans-8-chloro-5-methyl-1- [4- (pyridin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
tert-Butyl trans-8-chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylate ester,
trans-8-Chloro-1- [4- (5-chloro-pyridin-3-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene ,
trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzoazulene-5-carboxylic acid tert-butyl ester, trans- 8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride,
trans-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene,
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester,
trans-8-Chloro-1- [4- (6-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-Chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene hydrochloride salt,
trans-8-chloro-1- [4- (5-chloro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-Chloro-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrimidin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrazin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyrimidin-4-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-Chloro-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
trans-8-chloro-5-methyl-1- [4- (pyridazin-3-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
cis-8-Chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -4H, 6H-2,3,5,10b-tetraaza-benzo [e] azulene-5-carboxylic acid tert-butyl ester ,
cis-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
cis-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-chloro-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-5- (2,2-difluoro-ethyl) -1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3 5,10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-5- (2-fluoro-ethyl) -1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5 10b-tetraaza-benzo [e] azulene,
trans-8-Chloro-5-ethyl-1- [4- (3-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-5-ethyl-1- [4- (5-fluoro-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene,
trans-8-chloro-5-ethyl-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] Azulene, or
trans-8-chloro-5-methyl-1- [4- (6-methyl-pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [ e] selected from Azulene,
15. A compound according to any one of claims 1-14.   The compound is trans-8-chloro-5-methyl-1- (4-phenoxy-cyclohexyl) -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulene or trans-8 -Chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene The compound of any one of 1-15.   From the compound trans-8-chloro-5-methyl-1- [4- (pyridin-2-yloxy) -cyclohexyl] -5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene 17. A compound according to any one of claims 1 to 16, which is selected. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 17, comprising the formula (II):

A compound represented by formula (III):

A method comprising the step of reacting with a compound of formula (I) wherein R ¹ , R ² and R ³ are as defined in claim 1.   A compound of formula (I) when obtained by the method of claim 18.   18. A compound of formula (I) according to any one of claims 1 to 17 for use as a therapeutically active substance.   Dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive 18. A compound of formula (I) according to any one of claims 1 to 17 for use in the prevention or treatment of behavior.   A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17.   Dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive 23. The pharmaceutical composition according to claim 22, which is useful for behavioral prevention or treatment.   Dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive Use of a compound of formula (I) according to any one of claims 1 to 17 for the manufacture of a medicament for the prevention or treatment of behavior.   Dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, vasopressin secretion abnormalities, cirrhosis, nephrotic syndrome, anxiety, depressive disorder, obsessive compulsive disorder, autism spectrum disorder, schizophrenia and aggressive A method for therapeutic and / or prophylactic treatment of behavior comprising administering to a human or animal a compound according to any one of claims 1-17.   The invention described earlier in this specification.